{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T01:59:14Z","timestamp":1785376754773,"version":"3.55.0"},"reference-count":27,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T00:00:00Z","timestamp":1777939200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T00:00:00Z","timestamp":1777939200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24K0214524"],"award-info":[{"award-number":["24K0214524"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["22fk0108527"],"award-info":[{"award-number":["22fk0108527"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007263","name":"Astellas Foundation for Research on Metabolic Disorders","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007263","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Protein Science"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The intrinsic dynamic asymmetry between homologous PDZ domains in multidomain scaffold proteins offers insight into how they achieve multivalent partner recognition. Through a systematic x\u2010ray crystallographic analysis of tandem PDZ1\u2013PDZ2 domains in human syntenin\u20101 (SDCBP\/MDA\u20109), we solved nine high\u2010resolution structures and uncovered fundamental differences in conformational plasticity between these sequentially similar domains. Pairwise root mean square deviation (RMSD) analysis of 20 PDZ1 structures across multiple crystal forms revealed substantial structural variability concentrated in the Lys119\u2010Ile125 and Ala181\u2010Glu184 loops\u2014key regions governing ligand specificity within PDZ1's binding cleft\u2014whereas PDZ2 maintained remarkable structural conservation, indicating divergent evolutionary constraints on these tandem domains. Comparative analysis of isotropic B\u2010factors and multistructure RMSD highlighted the limitations of B\u2010factors alone and emphasized the value of multistructure comparisons for mapping dynamic landscapes. Molecular dynamics (MD) simulations implemented through GROMACS corroborate the crystallographic observations, showing elevated residue\u2010specific fluctuation values in PDZ1's ligand\u2010binding interface compared to analogous PDZ2 regions, and steady\u2010state heteronuclear NOE measurements support enhanced loop flexibility in PDZ1 relative to PDZ2. Together, these findings indicate that PDZ1's conformational diversity represents an inherent biophysical property rather than a crystallographic artifact, suggest a functional division of labor in which PDZ1's structural plasticity enables broad ligand recognition via conformational selection while PDZ2's rigid architecture stabilizes the tandem domain arrangement, and provide an atomic\u2010level framework for developing domain\u2010selective therapeutics targeting syntenin\u20101 in cancer, viral infection, and neurodevelopmental disorders.<\/jats:p>","DOI":"10.1002\/pro.70607","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T13:39:07Z","timestamp":1777988347000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Intrinsically dominant conformational diversity in\n                    <scp>PDZ1<\/scp>\n                    within the tandem\n                    <scp>PDZ1<\/scp>\n                    \u2013\n                    <scp>PDZ2<\/scp>\n                    of human syntenin\u20101 underlied by crystal structures"],"prefix":"10.1002","volume":"35","author":[{"given":"Natsuno","family":"Ando","sequence":"first","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences Nagoya University  Nagoya Aichi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3102-2945","authenticated-orcid":false,"given":"Yuya","family":"Hanazono","sequence":"additional","affiliation":[{"name":"Laboratory of Structural Biology, Medical Research Laboratory Institute of Integrated Research, Institute of Science  Bunkyo\u2010ku Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koya","family":"Sakuma","sequence":"additional","affiliation":[{"name":"Cellular and Structural Physiology Institute (CeSPI) Nagoya University  Nagoya Aichi 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