{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T14:39:00Z","timestamp":1771339140495,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1010794","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T00:00:00Z","timestamp":1672876800000}}],"reference-count":49,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T00:00:00Z","timestamp":1671580800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["1753167"],"award-info":[{"award-number":["1753167"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Signal Transducer and Activator of Transcription 3 (STAT3) plays a crucial role in cancer development and thus is a viable target for cancer treatment. STAT3 functions as a dimer mediated by phosphorylation of the SRC-homology 2 (SH2) domain, a key target for therapeutic drugs. While great efforts have been employed towards the development of compounds that directly target the SH2 domain, no compound has yet been approved by the FDA due to a lack of specificity and pharmacologic efficacy. Studies have shown that allosteric regulation of SH2 via the coiled-coil domain (CCD) is an alternative drug design strategy. Several CCD effectors have been shown to modulate SH2 binding and affinity, and at the time of writing at least one drug candidate has entered phase I clinical trials. However, the mechanism for SH2 regulation via CCD is poorly understood. Here, we investigate structural and dynamic features of STAT3 and compare the wild type to the reduced function variant D170A in order to delineate mechanistic differences and propose allosteric pathways. Molecular dynamics simulations were employed to explore conformational space of STAT3 and the variant, followed by structural, conformation, and dynamic analysis. The trajectories explored show distinctive conformational changes in the SH2 domain for the D170A variant, indicating long range allosteric effects. Multiple analyses provide evidence for long range communication pathways between the two STAT3 domains, which seem to be mediated by a rigid core which connects the CCD and SH2 domains via the linker domain (LD) and transmits conformational changes through a network of short-range interactions. The proposed allosteric mechanism provides new insight into the understanding of intramolecular signaling in STAT3 and potential pharmaceutical control of STAT3 specificity and activity.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1010794","type":"journal-article","created":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T18:37:55Z","timestamp":1671647875000},"page":"e1010794","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["Allosteric regulation in STAT3 interdomains is mediated by a rigid core: SH2 domain regulation by CCD in D170A variant"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8429-2239","authenticated-orcid":true,"given":"Tingting","family":"Zhao","sequence":"first","affiliation":[]},{"given":"Nischal","family":"Karki","sequence":"additional","affiliation":[]},{"given":"Brian D.","family":"Zoltowski","sequence":"additional","affiliation":[]},{"given":"Devin A.","family":"Matthews","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,12,21]]},"reference":[{"issue":"11","key":"pcbi.1010794.ref001","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1039\/b606246f","article-title":"Structure, function, and regulation of STAT proteins","volume":"2","author":"CP Lim","year":"2006","journal-title":"Molecular BioSystems"},{"issue":"5573","key":"pcbi.1010794.ref002","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1126\/science.1071545","article-title":"A Road Map for Those Who Don't Know JAK-STAT","volume":"296","author":"DS Aaronson","year":"2002","journal-title":"Science"},{"issue":"2","key":"pcbi.1010794.ref003","doi-asserted-by":"crossref","first-page":"65","DOI":"10.4161\/jkst.20045","article-title":"STAT1 and STAT3 in tumorigenesis","volume":"1","author":"L Avalle","year":"2012","journal-title":"JAK-STAT"},{"issue":"4","key":"pcbi.1010794.ref004","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1089\/jir.2015.0054","article-title":"STAT5 in Cancer and Immunity","volume":"36","author":"A Rani","year":"2016","journal-title":"Journal of Interferon & Cytokine Research"},{"issue":"4","key":"pcbi.1010794.ref005","doi-asserted-by":"crossref","first-page":"179","DOI":"10.4161\/trns.2.4.16614","article-title":"Changing the STATus quo in T helper cells","volume":"2","author":"GL Stritesky","year":"2011","journal-title":"Transcription"},{"issue":"D1","key":"pcbi.1010794.ref006","first-page":"D480","article-title":"UniProt: the universal protein knowledgebase in 2021","volume":"49","author":"A Bateman","year":"2020","journal-title":"Nucleic Acids Research"},{"issue":"6","key":"pcbi.1010794.ref007","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.3390\/ijms19061591","article-title":"Structural Biology of STAT3 and Its Implications for Anticancer Therapies Development","volume":"19","author":"J Sgrignani","year":"2018","journal-title":"International Journal of Molecular Sciences"},{"issue":"2","key":"pcbi.1010794.ref008","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/nrc1275","article-title":"The STATs of cancer \u2014 new molecular targets come of age","volume":"4","author":"H Yu","year":"2004","journal-title":"Nature Reviews Cancer"},{"issue":"11","key":"pcbi.1010794.ref009","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1038\/nrc2734","article-title":"STATs in cancer inflammation and immunity: a leading role for STAT3","volume":"9","author":"H Yu","year":"2009","journal-title":"Nature Reviews Cancer"},{"issue":"4","key":"pcbi.1010794.ref010","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/nrclinonc.2018.8","article-title":"Targeting the IL-6\/JAK\/STAT3 signalling axis in cancer","volume":"15","author":"DE Johnson","year":"2018","journal-title":"Nature Reviews Clinical Oncology"},{"issue":"5","key":"pcbi.1010794.ref011","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.ccell.2019.10.002","article-title":"A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo","volume":"36","author":"L Bai","year":"2019","journal-title":"Cancer Cell"},{"issue":"1","key":"pcbi.1010794.ref012","doi-asserted-by":"crossref","DOI":"10.1590\/1678-4685-gmb-2018-0160","article-title":"Targeting STAT-3 signaling pathway in cancer for development of novel drugs: Advancements and challenges","volume":"43","author":"S Arshad","year":"2020","journal-title":"Genetics and Molecular Biology"},{"issue":"2","key":"pcbi.1010794.ref013","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1006\/jmbi.2000.3765","article-title":"Mutational investigation of the specificity determining region of the src SH2 domain 1 1Edited by J. 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