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Modelling of the Complex between a 15‐Residue Peptide from mSos2 and the N‐Terminal SH3 Domain of Grb2 by Molecular‐Dynamics Simulation
Author(s) -
Calero Sofía,
Lago Santiago,
van Gunsteren Wilfred F.,
Daura Xavier
Publication year - 2004
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.200490044
Subject(s) - grb2 , sh3 domain , peptide , chemistry , polyproline helix , molecular dynamics , signal transducing adaptor protein , guanine nucleotide exchange factor , residue (chemistry) , biophysics , gtpase , biochemistry , proto oncogene tyrosine protein kinase src , receptor , biology , computational chemistry
Under specific conditions, the complex formed by the adaptor protein Grb2 and the guanine‐nucleotide exchange factor Sos2 is responsible for the activation of Ras, a low‐molecular‐weight GTPase involved in the control of cell proliferation and differentiation. The interaction between the N‐terminal SH3 domain of the mouse Grb2 and one of its potential target sequences in the mouse, Sos2, a 15‐residue peptide corresponding to residues 1264–1278, had been studied by NMR. However, the resulting data provided very limited information on the structure of the peptide and its interaction with the protein. Here, we present results from a molecular‐dynamics simulation aimed at producing a realistic, atomic model for the interaction between the N‐terminal SH3 domain of Grb2 and the SPLLPKLPPKTYKRE peptide from Sos2. In the simulation, the peptide adopts an extended conformation over the protein's binding surface. The proposed polyproline‐type‐II helicity appears only locally, and the peptide displays substantial flexibility. It is found that the peptide residues Lys 10 to Tyr 12 could be responsible for most of the specificity of the interaction.