Hostname: page-component-cd9895bd7-gbm5v Total loading time: 0 Render date: 2024-12-25T07:57:01.021Z Has data issue: false hasContentIssue false
  • English
  • Français

Features of protein–protein interactions that translate into potent inhibitors: topology, surface area and affinity

Published online by Cambridge University Press:  26 July 2012

Matthew C. Smith  and
Jason E. Gestwicki
Matthew C. Smith
Affiliation:
Departments of Pathology and Biological Chemistry and The Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
Jason E. Gestwicki*
Affiliation:
Departments of Pathology and Biological Chemistry and The Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
*
*Corresponding author: Jason E. Gestwicki, Departments of Pathology and Biological Chemistry and The Life Sciences Institute, University of Michigan, Life Sciences Institute, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA. E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Protein–protein interactions (PPIs) control the assembly of multi-protein complexes and, thus, these contacts have enormous potential as drug targets. However, the field has produced a mix of both exciting success stories and frustrating challenges. Here, we review known examples and explore how the physical features of a PPI, such as its affinity, hotspots, off-rates, buried surface area and topology, might influence the chances of success in finding inhibitors. This analysis suggests that concise, tight binding PPIs are most amenable to inhibition. However, it is also clear that emerging technical methods are expanding the repertoire of ‘druggable’ protein contacts and increasing the odds against difficult targets. In particular, natural product-like compound libraries, high throughput screens specifically designed for PPIs and approaches that favour discovery of allosteric inhibitors appear to be attractive routes. The first group of PPI inhibitors has entered clinical trials, further motivating the need to understand the challenges and opportunities in pursuing these types of targets.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 14 , March 2012 , e16
Copyright
Copyright © Cambridge University Press 2012

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

References

1Stelzl, U. et al. (2005) A human protein–protein interaction network: a resource for annotating the proteome. Cell 122, 957-968CrossRefGoogle ScholarPubMed
2Rual, J.-F. et al. (2005) Towards a proteome-scale map of the human protein-protein interaction network. Nature 437, 1173-1178CrossRefGoogle ScholarPubMed
3Jones, S. and Thornton, J.M. (1996) Principles of protein–protein interactions. Proceedings of the National Academy of Sciences of the United States of America 93, 13-20CrossRefGoogle ScholarPubMed
4Gavin, A.C. et al. (2002) Functional organization of the yeast proteome by systematic analysis of protein complexes. Nature 415, 141-147CrossRefGoogle ScholarPubMed
5Ryan, D.P. and Matthews, J.M. (2005) Protein–protein interactions in human disease. Current Opinion in Structural Biology 15, 441-446CrossRefGoogle ScholarPubMed
6Kuriyan, J. and Eisenberg, D. (2007) The origin of protein interactions and allostery in colocalization. Nature 450, 983-990CrossRefGoogle ScholarPubMed
7Balch, W.E. and Yates, J.R. (2011) Application of mass spectrometry to study proteomics and interactomics in cystic fibrosis. Cystic Fibrosis: Diagnosis and Protocols, Vol Ii: Methods and Resources to Understand Cystic Fibrosis 742, 227-247CrossRefGoogle ScholarPubMed
8Vidal, M., Cusick, M. and Barabasi, A.-L. (2011) Interactome networks and human disease. Cell 144, 986-998CrossRefGoogle ScholarPubMed
9Arkin, M. (2005) Protein-protein interactions and cancer: small molecules going in for the kill. Current Opinion in Chemical Biology 9, 317-324CrossRefGoogle ScholarPubMed
10Morelli, X., Bourgeas, R. and Roche, P. (2011) Chemical and structural lessons from recent successes in protein–protein interaction inhibition (2p2i). Current Opinion in Chemical Biology 15, 475-481CrossRefGoogle ScholarPubMed
11Thangudu, R.R. et al. (2012) Modulating protein–protein interactions with small molecules: the importance of binding hotspots. Journal of Molecular Biology 415, 443-453CrossRefGoogle ScholarPubMed
12Reynolds, K., McLaughlin, R. and Ranganathan, R. (2011) Hot spots for allosteric regulation on protein surfaces. Cell 147, 1564-1575CrossRefGoogle ScholarPubMed
13Yang, C.-Y. and Wang, S. (2010) Computational analysis of protein hotspots. ACS Medicinal Chemistry Letters 1, 125-129CrossRefGoogle ScholarPubMed
14Geppert, T. et al. (2011) Context-based identification of protein–protein interfaces and ‘hot-spot’ residues. Chemistry and Biology 18, 344-353CrossRefGoogle ScholarPubMed
15Reichmann, D. et al. (2005) The modular architecture of protein-protein binding interfaces. Proceedings of the National Academy of Sciences of the United States of America 102, 57-62CrossRefGoogle ScholarPubMed
16Wells, J.A. and McClendon, C.L. (2007) Reaching for high-hanging fruit in drug discovery at protein–protein interfaces. Nature 450, 1001-1009CrossRefGoogle ScholarPubMed
17Keskin, O. et al. (2008) Principles of protein–protein interactions: what are the preferred ways for proteins to interact? Chemical Reviews 108, 1225-1244CrossRefGoogle ScholarPubMed
18Berg, T. (2003) Modulation of protein–protein interactions with small organic molecules. Angewandte Chemie International Edition 42, 2462-2481CrossRefGoogle ScholarPubMed
19Veselovsky, A.V. et al. (2002) Protein–protein interactions: mechanisms and modification by drugs. Journal of Molecular Recognition 15, 405-422CrossRefGoogle ScholarPubMed
20Gordo, S. and Giralt, E. (2009) Knitting and untying the protein network: modulation of protein ensembles as a therapeutic strategy. Protein Science 18, 481-493CrossRefGoogle ScholarPubMed
21Meireles, L.M.C. and Mustata, G. (2011) Discovery of modulators of protein–protein interactions: current approaches and limitations. Current Topics in Medicinal Chemistry 11, 248-257CrossRefGoogle ScholarPubMed
22Toogood, P.L. (2002) Inhibition of protein–protein association by small molecules: approaches and progress. Journal of Medicinal Chemistry 45, 1543-1558CrossRefGoogle ScholarPubMed
23Arkin, M.R. and Whitty, A. (2009) The road less traveled: modulating signal transduction enzymes by inhibiting their protein–protein interactions. Current Opinion in Chemical Biology 13, 284-290CrossRefGoogle ScholarPubMed
24Cheng, A.C. et al. (2007) Structure-based maximal affinity model predicts small-molecule druggability. Nature Biotechnology 25, 71-75CrossRefGoogle ScholarPubMed
25Lipinski, C.A. et al. (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews 46, 3-26CrossRefGoogle ScholarPubMed
26Clackson, T. and Wells, J. (1995) A hot spot of binding energy in a hormone–receptor interface. Science 267, 383-386CrossRefGoogle Scholar
27Erlanson, D.A., Wells, J.A. and Braisted, A.C. (2004) Tethering: fragment-based drug discovery. Annual Review of Biophysics and Biomolecular Structure 33, 199-223CrossRefGoogle ScholarPubMed
28Valkov, E. et al. (2012) Targeting Protein–Protein Interactions and Fragment-Based Drug Discovery. In Fragment-Based Drug Discovery and X-Ray Crystallography (Hyvönen, M. and Davies, T.G. eds), pp. 145-179, Springer, Berlin/HeidelbergGoogle Scholar
29Hopkins, A.L. and Groom, C.R. (2002) The druggable genome. Nature Reviews Drug Discovery 1, 727-730CrossRefGoogle ScholarPubMed
30Jochim, A.L. and Arora, P.S. (2010) Systematic analysis of helical protein interfaces reveals targets for synthetic inhibitors. ACS Chemical Biology 5, 919-923CrossRefGoogle ScholarPubMed
31Walters, W.P., Murcko, A. and Murcko, M.A. (1999) Recognizing molecules with drug-like properties. Current Opinion in Chemical Biology 3, 384-387CrossRefGoogle ScholarPubMed
32Schreiber, S.L. (2000) Target-oriented and diversity-oriented organic synthesis in drug discovery. Science 287, 1964-1969CrossRefGoogle ScholarPubMed
33Xu, Y. et al. (2006) A credit-card library approach for disrupting protein–protein interactions. Bioorganic and Medicinal Chemistry 14, 2660-2673CrossRefGoogle ScholarPubMed
34Reayi, A. and Arya, P. (2005) Natural product-like chemical space: search for chemical dissectors of macromolecular interactions. Current Opinion in Chemical Biology 9, 240-247CrossRefGoogle ScholarPubMed
35Woodman, R. et al. (2005) Design and validation of a neutral protein scaffold for the presentation of peptide aptamers. Journal of Molecular Biology 352, 1118-1133CrossRefGoogle ScholarPubMed
36Kritzer, J.A. et al. (2006) Miniature protein inhibitors of the P53–Hdm2 interaction. ChemBioChem 7, 29-31CrossRefGoogle ScholarPubMed
37Verdine, G.L. and Hilinski, G.J. (2012) Chapter one – stapled peptides for intracellular drug targets. In Methods in Enzymology (Wittrup, K.D. and Gregory, L.V. eds), pp. 3-33, Academic PressGoogle Scholar
38Walensky, L.D. et al. (2004) Activation of apoptosis in vivo by a hydrocarbon-stapled Bh3 helix. Science 305, 1466-1470CrossRefGoogle ScholarPubMed
39Zhang, H. et al. (2008) A cell-penetrating helical peptide as a potential Hiv-1 inhibitor. Journal of Molecular Biology 378, 565-580CrossRefGoogle ScholarPubMed
40Horswill, A.R., Savinov, S.N. and Benkovic, S.J. (2004) A systematic method for identifying small-molecule modulators of protein–protein interactions. Proceedings of the National Academy of Sciences of the United States of America 101, 15591-15596CrossRefGoogle ScholarPubMed
41Ruvo, M. et al. (2011) Branched peptides for the modulation of protein–protein interactions: more arms are better than one? Current Medicinal Chemistry 18, 2429-2437CrossRefGoogle ScholarPubMed
42Gestwicki, J.E., Crabtree, G.R. and Graef, I.A. (2004) Harnessing chaperones to generate small-molecule inhibitors of amyloid B aggregation. Science 306, 865-869CrossRefGoogle Scholar
43Gestwicki, J.E. and Marinec, P.S. (2007) Chemical control over protein–protein interactions: beyond inhibitors. Combinatorial Chemistry and High Throughput Screening 10, 667-675CrossRefGoogle ScholarPubMed
44DeLano, W.L. et al. (2000) Convergent solutions to binding at a protein–protein interface. Science 287, 1279-1283CrossRefGoogle Scholar
45Sprinzak, E., Altuvia, Y. and Margalit, H. (2006) Characterization and prediction of protein–protein interactions within and between complexes. Proceedings of the National Academy of Sciences of the United States of America 103, 14718-14723CrossRefGoogle ScholarPubMed
46Lessard, J.A. and Crabtree, G.R. (2010) Chromatin regulatory mechanisms in pluripotency. In Annual Review of Cell and Developmental Biology, vol. 26 (Schekman, R.G.L.L.R. ed.), pp. 503-532Google Scholar
47Hohfeld, J., Cyr, D.M. and Patterson, C. (2001) From the cradle to the grave: molecular chaperones that may choose between folding and degradation. EMBO Reports 2, 885-890CrossRefGoogle Scholar
48Cohen, E.A. et al. (1986) Specific-inhibition of herpesvirus ribonucleotide reductase by a nonapeptide derived from the carboxy terminus of subunit-2. Nature 321, 441-443CrossRefGoogle ScholarPubMed
49Dutia, B.M. et al. (1986) Specific-inhibition of herpesvirus ribonucleotide reductase by synthetic peptides. Nature 321, 439-441CrossRefGoogle ScholarPubMed
50Bourgeas, R. et al. (2010) Atomic Analysis of Protein–Protein Interfaces with Known Inhibitors: The 2p2i Database. PLoS ONE 5, e9598CrossRefGoogle ScholarPubMed
51Higueruelo, A.P. et al. (2009) Atomic interactions and profile of small molecules disrupting protein–protein interfaces: the timbal database. Chemical Biology and Drug Design 74, 457-467CrossRefGoogle ScholarPubMed
52Tilley, J.W. et al. (1997) Identification of a small molecule inhibitor of the Il-2/Il-2rα receptor interaction which binds to Il-2. Journal of the American Chemical Society 119, 7589-7590CrossRefGoogle Scholar
53Raimundo, B.C. et al. (2004) Integrating fragment assembly and biophysical methods in the chemical advancement of small-molecule antagonists of Il-2: an approach for inhibiting protein-protein interactions. Journal of Medicinal Chemistry 47, 3111-3130CrossRefGoogle ScholarPubMed
54Thanos, C.D., DeLano, W.L. and Wells, J.A. (2006) Hot-spot mimicry of a cytokine receptor by a small molecule. Proceedings of the National Academy of of the United States of America 103, 15422-15427CrossRefGoogle ScholarPubMed
55Fry, D.C. et al. (2004) Nmr structure of a complex between Mdm2 and a small molecule inhibitor. Journal of Biomolecular NMR 30, 163-173CrossRefGoogle Scholar
56Vassilev, L.T. et al. (2004) In vivo activation of the p53 pathway by small-molecule antagonists of Mdm2. Science 303, 844-848CrossRefGoogle ScholarPubMed
57Ding, K. et al. (2005) Structure-based design of potent non-peptide Mdm2 inhibitors. Journal of the American Chemical Society 127, 10130-10131CrossRefGoogle ScholarPubMed
58Shangary, S. et al. (2008) Temporal activation of P53 by a specific Mdm2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proceedings of the National Academy of Sciences of the United States of America 105, 3933-3938CrossRefGoogle ScholarPubMed
59Wang, G.P. et al. (2006) Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins. Journal of Medicinal Chemistry 49, 6139-6142CrossRefGoogle ScholarPubMed
60Bruncko, M. et al. (2007) Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-Xl. Journal of Medicinal Chemistry 50, 641-662CrossRefGoogle ScholarPubMed
61Oltersdorf, T. et al. (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435, 677-681CrossRefGoogle ScholarPubMed
62Murray, C.W. and Rees, D.C. (2009) The rise of fragment-based drug discovery. Nat Chem 1, 187-192CrossRefGoogle ScholarPubMed
63Gorczynski, M.J. et al. (2007) Allosteric inhibition of the protein–protein interaction between the leukemia-associated proteins Runx1 and Cbf beta. Chemistry and Biology 14, 1186-1197CrossRefGoogle Scholar
64Grembecka, J. et al. (2012) Menin-Mll inhibitors reverse oncogenic activity of Mll fusion proteins in Leukemia. Nature Chemical Biology 8, 277-284CrossRefGoogle ScholarPubMed
65Frankel, A.D. and Young, J.A.T. (1998) Hiv-1: fifteen proteins and an Rna. Annual Review of Biochemistry 67, 1-25CrossRefGoogle Scholar
66Weber, I.T. (1990) Comparison of the crystal-structures and intersubunit interactions of human immunodeficiency and rous-sarcoma virus proteases. Journal of Biological Chemistry 265, 10492-10496CrossRefGoogle ScholarPubMed
67Zhang, Z.Y. et al. (1991) Dissociative inhibition of dimeric enzymes – kinetic characterization of the inhibition of Hiv-1 protease by its cooh-terminal tetrapeptide. Journal of Biological Chemistry 266, 15591-15594CrossRefGoogle ScholarPubMed
68Ding, J. et al. (1994) Buried surface analysis of Hiv-1 reverse transcriptase P66/P51 heterodimer and its interaction with Dsdna template/primer. Journal of Molecular Recognition 7, 157-161CrossRefGoogle ScholarPubMed
69Divita, G., Restle, T. and Goody, R.S. (1993) Characterization of the dimerization process of Hiv-1 reverse-transcriptase heterodimer using intrinsic protein fluorescence. FEBS Letters 324, 153-158CrossRefGoogle ScholarPubMed
70Fan, X., Flentke, G.R. and Rich, D.H. (1998) Inhibition of Hiv-1 protease by a subunit of didemnaketal A. Journal of the American Chemical Society 120, 8893-8894CrossRefGoogle Scholar
71Quere, L., Wenger, T. and Schramm, H.J. (1996) Triterpenes as potential dimerization inhibitors of Hiv-1 protease. Biochemical and Biophysical Research Communications 227, 484-488CrossRefGoogle ScholarPubMed
72Balzarini, J. et al. (1992) 2′,5′-Bis-O-(tert-butyldimethylsilyl)-3′-spiro-5″-(4″-amino-1″,2″- oxathiole-2″,2′-dioxide)pyrimidine (Tsao) nucleoside analogues: highlyselective inhibitors of human immunodeficiency virus type 1 that are targeted at the viral reverse transcriptase. Proceedings of the National Academy of Sciences of the United States of America 89, 4392-4396CrossRefGoogle Scholar
73Bonache, M.a.-C. et al. (2005) Improving the antiviral efficacy and selectivity of Hiv-1 reverse transcriptase inhibitor Tsao-T by the introduction of functional groups at the N-3 position. Journal of Medicinal Chemistry 48, 6653-6660CrossRefGoogle ScholarPubMed
74Graham, T.A. et al. (2000) Crystal structure of a B-catenin/Tcf complex. Cell 103, 885-896CrossRefGoogle Scholar
75Lepourcelet, M. et al. (2004) Small-molecule antagonists of the oncogenic Tcf/B–catenin protein complex. Cancer Cell 5, 91-102CrossRefGoogle Scholar
76Tian, W. et al. (2012) Structure-based discovery of a novel inhibitor targeting the B-catenin/Tcf4 interaction. Biochemistry 51, 724-731CrossRefGoogle Scholar
77Amin, A.R. and Abramson, S.B. (1998) The role of nitric oxide in articular cartilage breakdown in osteoarthritis. Current Opinion in Rheumatology 10, 263-268CrossRefGoogle ScholarPubMed
78Nathan, C. and Xie, Q.W. (1994) Nitric-oxide synthases – roles, tolls and controls. Cell 78, 915-918CrossRefGoogle ScholarPubMed
79McMillan, K. et al. (2000) Allosteric inhibitors of inducible nitric oxide synthase dimerization discovered via combinatorial chemistry. Proceedings of the National Academy of Sciences of the United States of America 97, 1506-1511CrossRefGoogle ScholarPubMed
80Lee, G.M. and Craik, C.S. (2009) Trapping moving targets with small molecules. Science 324, 213-215CrossRefGoogle ScholarPubMed
81Fieber, W. et al. (2001) Structure, function and dynamics of the dimerization and DNA-binding domain of oncogenic transcription factor V-Myc. Journal of Molecular Biology 307, 1395-1410CrossRefGoogle ScholarPubMed
82Kiessling, A. et al. (2006) Selective inhibition of C-Myc/Max dimerization and DNA binding by small molecules. Chemistry and Biology 13, 745-751CrossRefGoogle ScholarPubMed
83Silvian, L.F. et al. (2011) Small molecule inhibition of the Tnf family cytokine Cd40 Ligand through a subunit fracture mechanism. ACS Chemical Biology 6, 636-647CrossRefGoogle ScholarPubMed
84He, M.M. et al. (2005) Small-molecule inhibition of Tnf-Alpha. Science 310, 1022-1025CrossRefGoogle ScholarPubMed
85Magliery, T.J. et al. (2005) Detecting protein–protein interactions with a green fluorescent protein fragment reassembly trap: scope and mechanism. Journal of the American Chemical Society 127, 146-157CrossRefGoogle Scholar
86Liu, B. et al. (2007) Label transfer chemistry for the characterization of protein-protein interactions. Journal of the American Chemical Society 129, 12348-12349CrossRefGoogle ScholarPubMed
87Heeres, J.T. et al. (2009) Identifying modulators of protein–protein interactions using photonic crystal biosensors. Journal of the American Chemical Society 131, 18202-18203CrossRefGoogle ScholarPubMed
88Porter, J.R. et al. (2008) A general and rapid cell-free approach for the interrogation of protein–protein, protein–DNA, and protein–Rna interactions and their antagonists utilizing split-protein reporters. Journal of the American Chemical Society 130, 6488-6497CrossRefGoogle ScholarPubMed
89Moerke, N.J. et al. (2007) Small-molecule inhibition of the interaction between the translation initiation factors Eif4e and Eif4g. Cell 128, 257-267CrossRefGoogle ScholarPubMed
90Roman, D.L. et al. (2007) Identification of small-molecule inhibitors of Rgs4 using a high-throughput flow cytometry protein interaction assay. Molecular Pharmacology 71, 169-175CrossRefGoogle ScholarPubMed
91Potashman, M.H. and Duggan, M.E. (2009) Covalent modifiers: an orthogonal approach to drug design. Journal of Medicinal Chemistry 52, 1231-1246CrossRefGoogle ScholarPubMed
92Reinke, A.A. and Gestwicki, J.E. (2011) Insight into amyloid structure using chemical probes. Chemical Biology and Drug Design 77, 399-411CrossRefGoogle ScholarPubMed
93Eisenberg, D. and Jucker, M. (2012) The amyloid state of proteins in human diseases. Cell 148, 1188-203CrossRefGoogle ScholarPubMed
94Findeis, M.A. (2000) Approaches to discovery and characterization of inhibitors of amyloid beta-peptide polymerization. Biochimica et Biophysica Acta-Molecular Basis of Disease 1502, 76-84CrossRefGoogle ScholarPubMed
95Lee, V.M.Y. (2002) Amyloid binding ligands as Alzheimer's disease therapies. Neurobiology of Aging 23, 1039-1042CrossRefGoogle ScholarPubMed
96Bose, M. et al. (2005) ‘Nature-inspired’ drug-protein complexes as inhibitors of a beta aggregation. Biochemical Society Transactions 33, 543-547CrossRefGoogle Scholar
97Roberts, B.E. et al. (2009) A synergistic small-molecule combination directly eradicates diverse prion strain structures. Nature Chemical Biology 5, 936-946CrossRefGoogle ScholarPubMed
98Schmid, E.M. and McMahon, H.T. (2007) Integrating molecular and network biology to decode endocytosis. Nature 448, 883-888CrossRefGoogle ScholarPubMed
99von Kleist, L. et al. (2011) Role of the clathrin terminal domain in regulating coated pit dynamics revealed by small molecule inhibition. Cell 146, 471-484CrossRefGoogle ScholarPubMed
100Lee, L.W. and Mapp, A.K. (2010) Transcriptional switches: chemical approaches to gene regulation. Journal of Biological Chemistry 285, 11033-11038CrossRefGoogle ScholarPubMed
101Buhrlage, S.J. et al. (2009) Amphipathic small molecules mimic the binding mode and function of endogenous transcription factors. ACS Chemical Biology 4, 335-344CrossRefGoogle ScholarPubMed
102Casey, R.J. et al. (2009) Expanding the repertoire of small molecule transcriptional activation domains. Bioorganic and Medicinal Chemistry 17, 1034-1043CrossRefGoogle ScholarPubMed
103Boriack-Sjodin, P.A. et al. (1998) The structural basis of the activation of Ras by Sos. Nature 394, 337-343CrossRefGoogle ScholarPubMed
104Sondermann, H. et al. (2004) Structural analysis of autoinhibition in the Ras activator son of sevenless. Cell 119, 393-405CrossRefGoogle ScholarPubMed
105Patgiri, A. et al. (2011) An orthosteric inhibitor of the Ras–Sos INteraction. Nature Chemical Biology 7, 585-587CrossRefGoogle ScholarPubMed
106Maurer, T. et al. (2012) Small-molecule ligands bind to a distinct pocket in Ras and inhibit Sos-mediated nucleotide exchange activity. Proceedings of the National Academy of Sciences of the United States of America 109, 5299-5304CrossRefGoogle ScholarPubMed
107Kiessling, L.L., Gestwicki, J.E. and Strong, L.E. (2006) Synthetic multivalent ligands as probes of signal transduction. Angewandte Chemie International Edition 45, 2348-2368CrossRefGoogle ScholarPubMed
108Evans, C.G., Chang, L. and Gestwicki, J.E. (2010) Heat shock protein 70 (Hsp70) as an emerging drug target. Journal of Medicinal Chemistry 53, 4585-4602CrossRefGoogle ScholarPubMed
109Patury, S., Miyata, Y. and Gestwicki, J.E. (2009) Pharmacological targeting of the Hsp70 chaperone. Current Topics in Medicinal Chemistry 9, 1337-1351CrossRefGoogle ScholarPubMed
110Brodsky, J.L. and Chiosis, G. (2006) Hsp70 molecular chaperones: emerging roles in human disease and identification of small molecule modulators. Current Topics in Medicinal Chemistry 6, 1215-1225CrossRefGoogle ScholarPubMed
111Brandt, G.E.L. and Blagg, B.S.J. (2009) Alternate strategies of Hsp90 modulation for the treatment of cancer and other diseases. Current Topics in Medicinal Chemistry 9, 1447-1461CrossRefGoogle ScholarPubMed
112Powers, M.V. and Workman, P. (2007) Inhibitors of the heat shock response: biology and pharmacology. FEBS Letters 581, 3758-3769CrossRefGoogle ScholarPubMed
113Hartl, F.U. and Hayer-Hartl, M. (2009) Converging concepts of protein folding in vitro and in vivo. Nature Structural and Molecular Biology 16, 574-581CrossRefGoogle ScholarPubMed
114Meimaridou, E., Gooljar, S.B. and Chapple, J.P. (2009) From hatching to dispatching: the multiple cellular roles of the Hsp70 molecular chaperone machinery. Journal of Molecular Endocrinology 42, 1-9CrossRefGoogle ScholarPubMed
115Massey, A.J. (2010) Atpases as drug targets: insights from heat shock proteins 70 and 90. Journal of Medicinal Chemistry 53, 7280-7286CrossRefGoogle Scholar
116Miyata, Y. et al. (2011) molecular chaperones and regulation of tau quality control: strategies for drug discovery in Tauopathies. Future Medicinal Chemistry 3, 1523-1537CrossRefGoogle ScholarPubMed
117Kampinga, H.H. and Craig, E.A. (2010) The Hsp70 chaperone machinery: j proteins as drivers of functional specificity. Nature Reviews Molecular Cell Biology 11, 579-592CrossRefGoogle ScholarPubMed
118Ahmad, A. et al. (2011) Heat shock protein 70 Kda Chaperone/Dnaj cochaperone complex employs an unusual dynamic interface. Proceedings of the National Academy of Sciences of the United States of America 108, 18966-18971CrossRefGoogle ScholarPubMed
119Jiang, J. et al. (2007) Structural basis of j cochaperone binding and regulation of Hsp70. Molecular Cell 28, 422-433CrossRefGoogle ScholarPubMed
120Harrison, C.J. et al. (1997) Crystal structure of the nucleotide exchange factor Grpe bound to the atpase domain of the molecular chaperone dnak. Science 276, 431-435CrossRefGoogle Scholar
121Schmid, A.B. et al. (2012) The architecture of functional modules in the Hsp90 co-chaperone Sti1/hop. EMBO Journal 31, 1506-1517CrossRefGoogle ScholarPubMed
122Scheufler, C. et al. (2000) Structure of Tpr domain-peptide complexes: critical elements in the assembly of the Hsp70–Hsp90 multichaperone machine. Cell 101, 199-210CrossRefGoogle ScholarPubMed
123Wisen, S. et al. (2010) Binding of a small molecule at a protein–protein interface regulates the chaperone activity of Hsp70–Hsp40. ACS Chemical Biology 5, 611-622CrossRefGoogle Scholar
124Chang, L. et al. (2011) Chemical screens against a reconstituted multiprotein complex: myricetin blocks Dnaj regulation of Dnak through an allosteric mechanism. Chemistry and Biology 18, 210-221CrossRefGoogle ScholarPubMed
125Bhattacharya, A. et al. (2009) Allostery in Hsp70 chaperones is transduced by subdomain rotations. Journal of Molecular Biology 388, 475-490CrossRefGoogle ScholarPubMed
126Chang, L. et al. (2008) High-throughput screen for small molecules that modulate the atpase activity of the molecular chaperone dnak. Analytical Biochemistry 372, 167-176CrossRefGoogle ScholarPubMed
127Miyata, Y. et al. (2010) High-throughput screen for escherichia coli heat shock protein 70 (Hsp70/Dnak): atpase assay in low volume by exploiting energy transfer. Journal of Biomolecular Screening 15, 1211-1219CrossRefGoogle ScholarPubMed
128Leu, J.I.J. et al. (2009) A small molecule inhibitor of inducible heat shock protein 70. Molecular Cell 36, 15-27CrossRefGoogle ScholarPubMed
129Li, J., Soroka, J. and Buchner, J. (2012) The Hsp90 chaperone machinery: conformational dynamics and regulation by co-chaperones. Biochimica et Biophysica Acta (BBA) – Molecular Cell Research 1823, 624-635CrossRefGoogle ScholarPubMed
130Kamal, A., Boehm, M.F. and Burrows, F.J. (2004) Therapeutic and diagnostic implications of Hsp90 activation. Trends in Molecular Medicine 10, 283-290CrossRefGoogle ScholarPubMed
131Whitesell, L. and Lindquist, S.L. (2005) Hsp90 and the chaperoning of cancer. Nature Reviews. Cancer 5, 761-772CrossRefGoogle ScholarPubMed
132Porter, J.R., Fritz, C.C. and Depew, K.M. (2010) Discovery and development of Hsp90 inhibitors: a promising pathway for cancer therapy. Current Opinion in Chemical Biology 14, 412-420CrossRefGoogle ScholarPubMed
133Bagatell, R. et al. (2000) Induction of a heat shock factor 1-dependent stress response alters the cytotoxic activity of Hsp90-binding agents. Clinical Cancer Research 6, 3312-3318Google ScholarPubMed
134Donnelly, A. and Blagg, B.S.J. (2008) Novobiocin and additional inhibitors of the Hsp90 C-terminal nucleotide-binding pocket. Current Medicinal Chemistry 15, 2702-2717CrossRefGoogle ScholarPubMed
135Sreeramulu, S. et al. (2009) The human Cdc37.Hsp90 complex studied by heteronuclear Nmr spectroscopy. Journal of Biological Chemistry 284, 3885-3896CrossRefGoogle ScholarPubMed
136Meyer, P. et al. (2004) Structural basis for recruitment of the atpase activator Aha1 to the Hsp90 chaperone machinery. EMBO Journal 23, 511-519CrossRefGoogle Scholar
137Siligardi, G. et al. (2004) Co-chaperone regulation of conformational switching in the Hsp90 atpase cycle. Journal of Biological Chemistry 279, 51989-51998CrossRefGoogle ScholarPubMed
138Zhang, T. et al. (2009) Characterization of celastrol to inhibit Hsp90 and Cdc37 interaction. Journal of Biological Chemistry 284, 35381-35389CrossRefGoogle ScholarPubMed
139Sreeramulu, S. et al. (2009) Molecular mechanism of inhibition of the human protein complex Hsp90–Cdc37, a kinome chaperone–cochaperone, by triterpene celastrol. Angewandte Chemie International Edition 48, 5853-5855CrossRefGoogle ScholarPubMed
140Ardi, V.C. et al. (2011) Macrocycles that inhibit the binding between heat shock protein 90 and Tpr-containing proteins. ACS Chemical Biology 6, 1357-1366CrossRefGoogle ScholarPubMed
141Yi, F. and Regan, L. (2008) A novel class of small molecule inhibitors of Hsp90. ACS Chemical Biology 3, 645-654CrossRefGoogle ScholarPubMed
142Gandhi, P.S. et al. (2008) Structural identification of the pathway of long-range communication in an allosteric enzyme. Proceedings of the National Academy of Sciences of the United States of America 105, 1832-1837CrossRefGoogle Scholar
143Motlagh, H.N. and Hilser, V.J. (2012) Agonism/antagonism switching in allosteric ensembles. Proceedings of the National Academy of Sciences of the United States of America 109, 4134-4139CrossRefGoogle ScholarPubMed
144Chari, A. and Fischer, U. (2010) Cellular strategies for the assembly of molecular machines. Trends in Biochemical Sciences 35, 676-683CrossRefGoogle ScholarPubMed
145Peterson-Kaufman, K.J. et al. (2010) Nucleating the assembly of macromolecular complexes. ChemBioChem 11, 1955-1962CrossRefGoogle ScholarPubMed
146Good, M.C., Zalatan, J.G. and Lim, W.A. (2011) Scaffold proteins: hubs for controlling the flow of cellular information. Science 332, 680-686CrossRefGoogle ScholarPubMed
147Cardinale, D. et al. (2010) Homodimeric enzymes as drug targets. Current Medicinal Chemistry 17, 826-846CrossRefGoogle ScholarPubMed
148Panda, K. et al. (2002) Distinct dimer interaction and regulation in nitric-oxide synthase types I, Ii and Iii. Journal of Biological Chemistry 277, 31020-31030CrossRefGoogle ScholarPubMed
149Knapp, S. et al. (2001) Thermodynamics of the high-affinity interaction of Tcf4 with B-catenin. Journal of Molecular Biology 306, 1179-1189CrossRefGoogle Scholar
150Rickert, M. et al. (2005) The structure of interleukin-2 complexed with its alpha receptor. Science 308, 1477-1480CrossRefGoogle ScholarPubMed
151Braisted, A.C. et al. (2003) Discovery of a potent small molecule Il-2 inhibitor through fragment assembly. Journal of the American Chemical Society 125, 3714-3715CrossRefGoogle ScholarPubMed
152Yu, G.W. et al. (2006) The central region of Hdm2 provides a second binding site for P53. Proceedings of the National Academy of Sciences of the United States of America 103, 1227-1232CrossRefGoogle ScholarPubMed
153Kussie, P.H. et al. (1996) Structure of the Mdm2 oncoprotein bound to the P53 tumor suppressor transactivation domain. Science 274, 948-953CrossRefGoogle Scholar
154Grasberger, B.L. et al. (2005) Discovery and cocrystal structure of benzodiazepinedione Hdm2 antagonists that activate P53 in cells. Journal of Medicinal Chemistry 48, 909-912CrossRefGoogle ScholarPubMed
155Sattler, M. et al. (1997) Structure of Bcl-X(L)-Bak peptide complex: recognition between regulators of apoptosis. Science 275, 983-986CrossRefGoogle Scholar
156Tang, G. et al. (2007) Pyrogallol-based molecules as potent inhibitors of the antiapoptotic Bcl-2 proteins. Journal of Medicinal Chemistry 50, 1723-1726CrossRefGoogle ScholarPubMed
157Abbate, E.A., Berger, J.M. and Botchan, M.R. (2004) The X-ray structure of the papillomavirus helicase in complex with its molecular matchmaker E2. Genes and Development 18, 1981-1996CrossRefGoogle ScholarPubMed
158Wang, Y. et al. (2004) Crystal structure of the E2 transactivation domain of human papillomavirus type 11 bound to a protein interaction inhibitor. Journal of Biological Chemistry 279, 6976-6985CrossRefGoogle ScholarPubMed
159Edeling, M.A., Smith, C. and Owen, D. (2006) Life of a Clathrin coat: insights from Clathrin and Ap structures. Nature Reviews. Molecular Cell Biology 7, 32-44CrossRefGoogle ScholarPubMed
160Miele, A.E. et al. (2004) Two distinct interaction motifs in amphiphysin bind two independent sites on the Clathrin terminal domain [beta]-propeller. Nature Structural and Molecular Biology 11, 242-248CrossRefGoogle Scholar
161Siligardi, G. et al. (2002) Regulation of Hsp90 atpase activity by the co-chaperone Cdc37p/P50 Cdc37. Journal of Biological Chemistry 277, 20151-20159CrossRefGoogle Scholar
162Mosyak, L. et al. (2000) The bacterial cell-division protein Zipa and its interaction with an Ftsz fragment revealed by X-ray crystallography. EMBO Journal 19, 3179-3191CrossRefGoogle ScholarPubMed
163Rush, T.S. et al. (2005) A shape-based 3-D scaffold hopping method and its application to a bacterial protein, àíprotein interaction. Journal of Medicinal Chemistry 48, 1489-1495CrossRefGoogle Scholar
164Tesmer, J.J.G. et al. (1997) Structure of Rgs4 bound to Alf4-activated Gia1: stabilization of the transition state for Gtp hydrolysis. Cell 89, 251-261CrossRefGoogle Scholar
165Fernandez-Fernandez, M.R., Veprintsev, D.B. and Fersht, A.R. (2005) Proteins of the S100 family regulate the oligomerization of P53 tumor suppressor. Proceedings of the National Academy of Sciences of the United States of America 102, 4735-4740CrossRefGoogle ScholarPubMed
166Rust, R.R., Baldisseri, D.M. and Weber, D.J. (2000) Structure of the negative regulatory domain of P53 bound to S100b(Bβ). Nature Structural and Molecular Biology 7, 570-574Google Scholar
167Markowitz, J. et al. (2004) Identification and characterization of small molecule inhibitors of the calcium-dependent S100b-P53 tumor suppressor interaction. Journal of Medicinal Chemistry 47, 5085-5093CrossRefGoogle ScholarPubMed
168Mukai, Y. et al. (2010) Solution of the structure of the Tnf-Tnfr2 complex. Science Signalling 3, ra83-Google ScholarPubMed
169Aggarwal, B.B., Eessalu, T.E. and Hass, P.E. (1985) Characterization of receptors for human tumour necrosis factor and their regulation by Γ-interferon. Nature 318, 665-667CrossRefGoogle ScholarPubMed
170Pilger, B.D., Cui, C. and Coen, D.M. (2004) Identification of a small molecule that inhibits herpes simplex virus DNA polymerase subunit interactions and viral replication. Chemistry and Biology 11, 647-654CrossRefGoogle ScholarPubMed
171Vucic, D. et al. (2005) Engineering Ml-Iap to produce an extraordinarily potent caspase 9 inhibitor: implications for smac-dependent anti-apoptotic activity of Ml-Iap. Biochemical Journal 385, 11-20CrossRefGoogle ScholarPubMed
172Shiozaki, E.N. et al. (2003) Mechanism of Xiap-mediated inhibition of caspase-9. Molecular Cell 11, 519-527CrossRefGoogle ScholarPubMed
173Oost, T.K. et al. (2004) Discovery of potent antagonists of the antiapoptotic protein Xiap for the treatment of cancer. Journal of Medicinal Chemistry 47, 4417-4426CrossRefGoogle ScholarPubMed
174Cherepanov, P. et al. (2005) Structural basis for the recognition between Hiv-1 integrase and transcriptional coactivator P75. Proceedings of the National Academy of Sciences of the United States of America 102, 17308-17313CrossRefGoogle ScholarPubMed
175Tsiang, M. et al. (2009) Affinities between the binding PARTNERS of the Hiv-1 integrase dimer-lens epithelium-derived growth factor (in Dimer-Ledgf) complex. Journal of Biological Chemistry 284, 33580-33599CrossRefGoogle ScholarPubMed
176Christ, F. et al. (2010) Rational design of small-molecule inhibitors of the Ledgf/P75-integrase interaction and Hiv replication. Nature Chemical Biology 6, 442-448CrossRefGoogle ScholarPubMed
177Nair, S.K. and Burley, S.K. (2003) X-Ray structures of Myc-Max and Mad-Max recognizing DNA: molecular bases of regulation by proto-oncogenic transcription factors. Cell 112, 193-205CrossRefGoogle ScholarPubMed
178Hu, J., Banerjee, A. and Goss, D.J. (2005) Assembly of B/Hlh/Z proteins C-Myc, Max and Mad1 with Cognate DNA: importance of protein-protein and protein-DNA interactions. Biochemistry 44, 11855-11863CrossRefGoogle ScholarPubMed
179Stamper, C.C. et al. (2001) Crystal structure of the B7-1/Ctla-4 complex that inhibits human immune responses. Nature 410, 608-11CrossRefGoogle ScholarPubMed
180Erbe, D.V. et al. (2002) Small molecule ligands define a binding site on the immune regulatory protein B7.1. Journal of Biological Chemistry 277, 7363-7368CrossRefGoogle ScholarPubMed

Further reading

Bourgeas, R. et al. (2010) atomic analysis of protein–protein interfaces with known Inhibitors: the 2p2i database. PLoS One 5, e9598. http://2p2idb.cnrs-mrs.fr/CrossRefGoogle Scholar
Higueruelo, A.P. et al. (2009) Atomic interactions and profile of small molecules disrupting protein–protein interfaces: the timbal database. Chemical Biology and Drug Design 74, 457-467http://www.cryst.bioc.cam.ac.uk/databases/timbalCrossRefGoogle ScholarPubMed
Drewry, D.H. and Macarron, R. (2010) Enhancements of screening collections to address areas of unmet medical need: an industry perspective. Current Opinion in Chemical Biology 14, 289-298CrossRefGoogle ScholarPubMed
Uversky, V.N. (2012) Intrinsically disordered proteins and novel strategies for drug discovery. Expert Opinion on Drug Discovery 7, 475-488CrossRefGoogle ScholarPubMed
Jubb, H., et al. (2012) Structural biology and drug discovery for protein-protein interactions. Trends in Pharmacological Sciences 33(5): 241-248CrossRefGoogle ScholarPubMed
Verdine, G.L. et al. (2012) Chapter one – stapled peptides for intracellular drug targets. In Methods in Enzymology, pp. 3-33. Academic PressGoogle Scholar