The interaction of neurotrophins with the p75 NTR common neurotrophin receptor: A comprehensive molecular modeling study

Neurotrophins are a family of proteins with pleiotropic effects mediated by two distinct receptor types, namely the Trk family, and the common neurotrophin receptor p75 NTR . 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 p75 NTR is studied by molecular modeling based on X‐ray structures of the neurotrophins and the extracellular domain of p55 TNFR , a homologue of p75 NTR . 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 p75 NTR , 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 S c , 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 p75 NTR binding, directly participate in receptor binding in the framework of the model. Principal residues of the binding site of p75 NTR 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 p75 NTR binding site.