{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T13:12:26Z","timestamp":1779282746904,"version":"3.51.4"},"reference-count":64,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2008,6,5]],"date-time":"2008-06-05T00:00:00Z","timestamp":1212624000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Proteins"],"published-print":{"date-parts":[[2008,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>SH2 domains provide fundamental recognition sites in tyrosine kinase\u2010mediated 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\u2010binding 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\u2010v\u2010Src SH2 domain. This is accompanied by the analysis of backbone dynamics and p<jats:italic>K<\/jats:italic><jats:sub>a<\/jats:sub> values within the apo\u2010 and peptide\u2010bound 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\u2010terminal of the pY (pY + 3) or so\u2010called specificity determining region, is a large dynamic\u2010binding 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\u2010Src SH2 domain does not have a highly specific secondary\u2010binding site, which clearly presents a major hurdle to design selective inhibitors. Proteins 2008. \u00a9 2008 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/prot.22119","type":"journal-article","created":{"date-parts":[[2008,6,5]],"date-time":"2008-06-05T16:46:56Z","timestamp":1212684416000},"page":"929-940","source":"Crossref","is-referenced-by-count":23,"title":["Structure, dynamics, and binding thermodynamics of the v\u2010Src SH2 domain: Implications for drug design"],"prefix":"10.1002","volume":"73","author":[{"given":"Jonathan D.","family":"Taylor","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdessamad","family":"Ababou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Radwan R.","family":"Fawaz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher J.","family":"Hobbs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark A.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John E.","family":"Ladbury","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2008,6,5]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1083653"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(03)01077-8"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-5521(00)00067-3"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1021\/ar020167s"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90404-E"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.14.4.2777"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/proeng\/gzg025"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.2000.3765"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/358646a0"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi982974y"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0969-2126(98)00115-4"},{"key":"e_1_2_6_13_2","first-page":"330a","article-title":"Structural and thermodynamic analysis of the peptide binding specificity of the SH2 domain of Src kinase","volume":"82","author":"Lubman OY","year":"2002","journal-title":"Biophys J"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00156a002"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00187a015"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-5521(00)00090-9"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.17.9373"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S8756-3282(00)00427-0"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm0002681"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.21369"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm010927p"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(78)90024-7"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.75.4.2021"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(83)90073-9"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1208077"},{"key":"e_1_2_6_26_2","first-page":"165","volume-title":"Protein\u2013protein recognition in phosphotyrosine\u2010mediated intracellular signalling. 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