| abstract |
The present invention relates to a computational method for identifying the bioactive conformations of peptide domains, in particular, the geometries of complexes of neurotrophins and their receptors. The bioactive conformation of the Nerve Growth Factor (NGF) amino and carboxyl termini (Trk binding domain) was determined. The complex of the NGF termini splits into two distinct regions: a rigid region (residues 9-11 and 112'-118') and a flexible loop (residues 1-8). The geometry of the rigid region, which is maintained by electrostatic interaction between Glu11 and Arg118', is conserved in active molecules only. The separation of the flexible loop from the rigid region is necessary in order to eliminate an influence of the loop on the biologically active conformation of the rigid region. The present invention also relates to a method for identifying and theoretically modelling specific receptor binding sites for Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF) on their receptors, TrkA and TrkB, respectively. The present invention also relates to a method for identifying and theoretically modelling a receptor binding site for neurotrophins, such as NGF, BDNF, NT-3, and NT-4/5, of the common neurotrophin receptor p75NTR. |