{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T00:34:16Z","timestamp":1792197256788,"version":"4.4.0"},"reference-count":50,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2012,7,17]],"date-time":"2012-07-17T00:00:00Z","timestamp":1342483200000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Proteomics"],"published-print":{"date-parts":[[2012,7]]},"abstract":"ABL<\/jats:styled-content> tyrosine kinase inhibitor (TKI<\/jats:styled-content>) therapy induces clinical remission in chronic myeloid leukemia (CML<\/jats:styled-content>) patients but early relapses and later emergence of TKI<\/jats:styled-content>\u2010resistant disease remain problematic. We recently demonstrated that the AHI<\/jats:styled-content>\u20101 oncogene physically interacts with BCR<\/jats:styled-content>\u2010ABL<\/jats:styled-content> and JAK<\/jats:styled-content>2 and mediates cellular resistance to TKI<\/jats:styled-content> in CML<\/jats:styled-content> stem\/progenitor cells. We now show that deletion of the SH<\/jats:styled-content>3 domain of AHI<\/jats:styled-content>\u20101 significantly enhances apoptotic response of BCR<\/jats:styled-content>\u2010ABL<\/jats:styled-content>+<\/jats:sup> cells to TKI<\/jats:styled-content>s compared to cells expressing full\u2010length AHI<\/jats:styled-content>\u20101. We have also discovered a novel interaction between AHI<\/jats:styled-content>\u20101 and D<\/jats:styled-content>ynamin\u20102, a GTP<\/jats:styled-content>ase, through the AHI<\/jats:styled-content>\u20101 SH<\/jats:styled-content>3 domain. The crystal structure of the AHI<\/jats:styled-content>\u20101 SH<\/jats:styled-content>3 domain at 1.53\u2010\u00c5 resolution reveals that it adopts canonical SH<\/jats:styled-content>3 folding, with the exception of an unusual C<\/jats:styled-content>\u2010terminal \u03b1 helix. PD<\/jats:styled-content>1R<\/jats:styled-content> peptide, known to interact with the PI<\/jats:styled-content>3K SH<\/jats:styled-content>3 domain, was used to model the binding pattern between the AHI<\/jats:styled-content>\u20101 SH<\/jats:styled-content>3 domain and its ligands. These studies showed that an \u201cArg\u2010Arg\u2010Trp\u201d stack may form within the binding interface, providing a potential target site for designing specific drugs. The crystal structure of the AHI<\/jats:styled-content>\u20101 SH<\/jats:styled-content>3 domain thus provides a valuable tool for identification of key interaction sites in regulation of drug resistance and for the development of small molecule inhibitors for CML<\/jats:styled-content>.<\/jats:p>","DOI":"10.1002\/pmic.201100553","type":"journal-article","created":{"date-parts":[[2012,5,24]],"date-time":"2012-05-24T02:24:34Z","timestamp":1337826274000},"page":"2094-2106","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Molecular and structural characterization of the SH<\/scp>3 domain of AHI<\/scp>\u20101 in regulation of cellular resistance of BCR<\/scp>\u2010ABL<\/scp>+<\/sup> chronic myeloid leukemia cells to tyrosine kinase inhibitors"],"prefix":"10.1002","volume":"12","author":[{"given":"Xiaohu","family":"Liu","sequence":"first","affiliation":[{"name":"Terry Fox Laboratory British Columbia Cancer Agency 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