Neurotrophins are a family of proteins with pleiotropic
effects mediated by two distinct receptor types, namely
the Trk family, and the common neurotrophin receptor p75NTR.
Binding of four mammalian neurotrophins, nerve growth factor
(NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3
(NT-3), and neurotrophin-4/5 (NT-4/5), to p75NTR
is studied by molecular modeling based on X-ray structures
of the neurotrophins and the extracellular domain of p55TNFR,
a homologue of p75NTR. The model of neurotrophin/receptor
interactions suggests that the receptor binding domains
of neurotrophins (loops I and IV) are geometrically and
electrostatically complementary to a putative binding site
of p75NTR, formed by the second and part of
the third cysteine-rich domains. Geometric match of neurotrophin/receptor
binding domains in the complexes, as characterized by shape
complementarity statistic Sc, is comparable
to known protein/protein complexes. All charged residues
within the loops I and IV of the neurotrophins, previously
determined as being critical for p75NTR binding,
directly participate in receptor binding in the framework
of the model. Principal residues of the binding site of
p75NTR include Asp47, Lys56, Asp75, Asp76, Asp88,
and Glu89. The additional involvement of Arg80 and Glu53
is specific for NGF and BDNF, respectively, and Glu73 participates
in binding with NT-3 and NT-4/5. Neurotrophins are likely
to induce similar, but not identical, conformational changes
within the p75NTR binding site.