2008
DOI: 10.1002/prot.22119
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Structure, dynamics, and binding thermodynamics of the v‐Src SH2 domain: Implications for drug design

Abstract: 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… Show more

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Cited by 22 publications
(39 citation statements)
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“…This is consistent with the observation that phosphopeptides hardly bind to the ZAP-70 cSH2, whereas phosphate does so readily, in contrast to the cSH2 domain of Syk and to the nSH2 domains of both proteins (6,8,20,21). Structural flexibility is thought to relate to ligand diversity in other SH2 domains (22). For example, a similar mechanism of SH2 gating was recently suggested to regulate SHIP2 (23), differentiating it functionally from the closely related phosphatase SHIP1.…”
Section: Discussionsupporting
confidence: 85%
“…This is consistent with the observation that phosphopeptides hardly bind to the ZAP-70 cSH2, whereas phosphate does so readily, in contrast to the cSH2 domain of Syk and to the nSH2 domains of both proteins (6,8,20,21). Structural flexibility is thought to relate to ligand diversity in other SH2 domains (22). For example, a similar mechanism of SH2 gating was recently suggested to regulate SHIP2 (23), differentiating it functionally from the closely related phosphatase SHIP1.…”
Section: Discussionsupporting
confidence: 85%
“…Nonetheless, the internal dynamics of the pYEEI, cpYEEI, and fpYEEI Src SH2 complexes estimated from 15 N relaxation (Figure 2) and MD fluctuations (Figure 3) show only minor variations, which cannot convincingly account for the observed disparities in binding enthalpy of the three complexes. Previously reported NMR relaxation measurements for Src SH2 also suggest that main-chain flexibility varies little upon binding the canonical pYEEI peptide, with only minimal differences from residues scattered throughout the protein in the amplitude of motion specified from the Lipari-Szabo order parameter54. As such, we find no evidence that alternative conformational distributions occurring from ps-ns motions affect the time-average interaction energy with the three Src SH2 ligands.…”
Section: Discussionsupporting
confidence: 50%
“…The residue is universally conserved across SH2 domains. The structural importance of the hydrogen bonding between R175 and H201 has been supported by the acidic pKa of H201 Nδ, measured by NMR titration in Src SH254 and PLCγ72. A triad of hydrogen bonds between R175, H201, and E159 is argued to preorganize the R175 side-chain in its bound state geometry54.…”
Section: Discussionmentioning
confidence: 97%
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“…From a drug-development perspective, there may be distinct advantages to targeting domains other than SH2, a large domain family present throughout the genome. [2527] …”
mentioning
confidence: 99%