{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,25]],"date-time":"2026-01-25T16:39:38Z","timestamp":1769359178451,"version":"3.49.0"},"reference-count":26,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T00:00:00Z","timestamp":1769126400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"NIH","doi-asserted-by":"publisher","award":["R01 NS105874"],"award-info":[{"award-number":["R01 NS105874"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"NIH","doi-asserted-by":"publisher","award":["R01 GM122763"],"award-info":[{"award-number":["R01 GM122763"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000015","name":"U.S. Department of Energy","doi-asserted-by":"crossref","award":["DE-SC0012704"],"award-info":[{"award-number":["DE-SC0012704"]}],"id":[{"id":"10.13039\/100000015","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000015","name":"U.S. Department of Energy","doi-asserted-by":"crossref","award":["KP1605010"],"award-info":[{"award-number":["KP1605010"]}],"id":[{"id":"10.13039\/100000015","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Institutes of Health, National Institute of General Medical Sciences","award":["P30GM133893"],"award-info":[{"award-number":["P30GM133893"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Fyn is a Src-family tyrosine kinase implicated in synaptic dysfunction and neuroinflammation across multiple neurodegenerative disorders, including Alzheimer\u2019s disease (AD) and Parkinson\u2019s disease (PD). Saracatinib (AZD0530) is a potent Src-family inhibitor that has been explored as a repurposed therapeutic; however, its clinical utility is limited by poor kinase selectivity caused by high sequence conservation within Src-family ATP-binding sites. Here, we combine surface plasmon resonance (SPR) and X-ray crystallography to define saracatinib recognition by the Fyn kinase domain (KD). SPR single-cycle kinetics shows that saracatinib binds the isolated Fyn KD and full-length Fyn with low-nanomolar affinity, whereas dasatinib binds with subnanomolar affinity and markedly slower dissociation. We determined the crystal structure of the Fyn KD-saracatinib complex at 2.22 \u00c5 resolution. The kinase adopts an active-like conformation with the DFG motif and \u03b1C-helix in the \u2018in\u2019 state and a conserved \u03b23 \u03b1C Lys-Glu salt bridge. Saracatinib occupies the adenine and ribose pockets, and engages the hinge through direct and water-mediated hydrogen bonding while complementing a hydrophobic back pocket by van der Waals contacts. Comparison with reported saracatinib-bound structures of other kinases suggests that the active-state geometry observed for Fyn creates a pocket not observed in inactive-like complexes, providing a structural handle for designing Fyn-selective inhibitors. Comparison with all saracatinib-bound kinase co-structures currently available in the PDB (ALK2 and PKMYT1) indicates a conserved monodentate hinge binding mode but kinase-dependent \u03b1C-helix conformations, providing a structural rationale for designing Fyn-selective analogues.<\/jats:p>","DOI":"10.3390\/ijms27031143","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T10:41:34Z","timestamp":1769164894000},"page":"1143","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Fyn\u2013Saracatinib Complex Structure Reveals an Active State-like Conformation"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7298-6177","authenticated-orcid":false,"given":"Hai Minh","family":"Ta","sequence":"first","affiliation":[{"name":"Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Banumathi","family":"Sankaran","sequence":"additional","affiliation":[{"name":"Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric D.","family":"Roush","sequence":"additional","affiliation":[{"name":"Cytiva, Inc., Marlborough, MA 01752, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3175-5700","authenticated-orcid":false,"given":"Josephine C.","family":"Ferreon","sequence":"additional","affiliation":[{"name":"Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8538-1732","authenticated-orcid":false,"given":"Allan Chris M.","family":"Ferreon","sequence":"additional","affiliation":[{"name":"Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3152-0020","authenticated-orcid":false,"given":"Choel","family":"Kim","sequence":"additional","affiliation":[{"name":"Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s13195-015-0119-0","article-title":"A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer\u2019s disease","volume":"7","author":"Nygaard","year":"2015","journal-title":"Alzheimers Res. 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