Premium
Structure, dynamics, and binding thermodynamics of the v‐Src SH2 domain: Implications for drug design
Author(s) -
Taylor Jonathan D.,
Ababou Abdessamad,
Fawaz Radwan R.,
Hobbs Christopher J.,
Williams Mark A.,
Ladbury John E.
Publication year - 2008
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.22119
Subject(s) - proto oncogene tyrosine protein kinase src , sh2 domain , dynamics (music) , thermodynamics , domain (mathematical analysis) , chemistry , physics , biochemistry , mathematics , receptor , mathematical analysis , acoustics
SH2 domains provide fundamental recognition sites in tyrosine kinase‐mediated signaling pathways which, when aberrant, give rise to disease states such as cancer, diabetes, and immune deficiency. Designing specific inhibitors that target the SH2 domain‐binding site, however, have presented a major challenge. Despite well over a decade of intensive research, clinically useful SH2 domain inhibitors have yet to become available. A better understanding of the structural, dynamic, and thermodynamic contributions to ligand binding of individual SH2 domains will provide some insight as to whether inhibitor development is possible. We report the first high resolution solution structure of the apo‐v‐Src SH2 domain. This is accompanied by the analysis of backbone dynamics and p K a values within the apo‐ and peptide‐bound states. Our results indicate that the phosphotyrosine (pY) pocket is tightly structured and hence not adaptable to exogenous ligands. On the other hand, the pocket which accommodates residues proximal and C‐terminal of the pY (pY + 3) or so‐called specificity determining region, is a large dynamic‐binding surface. This appears to allow a high level of promiscuity in binding. Binding of a series of synthetic, phosphotyrosyl, peptidomimetic compounds designed to explore interactions in the pY + 3 pocket further demonstrates the ability of the SH2 domain to accommodate diverse ligands. The thermodynamic parameters of these interactions show dramatic enthalpy/entropy compensation. These data suggest that the v‐Src SH2 domain does not have a highly specific secondary‐binding site, which clearly presents a major hurdle to design selective inhibitors. Proteins 2008. © 2008 Wiley‐Liss, Inc.