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However, the molecular mechanism by which TS2\/16 modulates integrin affinity for extracellular ligands remains unclear. Using endogenous full-length \u03b15\u03b21 integrin purified from human placenta, we determined the structure of integrin \u03b15\u03b21 with fibronectin up to 2.61-\u00c5 resolution in the absence of TS2\/16, capturing the active form without its aid, and performed comparative B-factor-based analysis and CABS-Flex simulation with and without TS2\/16. Despite no global conformational differences, we found that TS2\/16 interacts with \u03b12 helix of the integrin \u03b21 subunit and contacts the C-terminus of \u03b13 helix, leading to a localized decrease in B factor. This interaction allosterically alters the dynamics of \u03b12\u2013\u03b13 loop despite not being in direct contact with TS2\/16. Notably, this loop directly engages fibronectin, and its dynamic change underlies the enhanced ligand-binding affinity and explains increased cell adhesion observed with TS2\/16. These findings reveal an allosteric mechanism of integrin regulation by TS2\/16 and offer insights for the rational design of therapeutic antibodies targeting integrin-mediated adhesion in pathological contexts such as inflammation and cancer.<\/jats:p>","DOI":"10.1093\/pnasnexus\/pgag044","type":"journal-article","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T10:57:42Z","timestamp":1771930662000},"source":"Crossref","is-referenced-by-count":1,"title":["Allosteric regulation of fibronectin binding by the anti-\u03b21 integrin antibody TS2\/16"],"prefix":"10.1093","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-0494-2174","authenticated-orcid":false,"given":"Jienyu","family":"Ding","sequence":"first","affiliation":[{"name":"Laboratory of Structural Cell Biology, National Heart, Lung, and Blood Institute, National Institutes of Health , 50 South Dr, Bethesda, MD 20892 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