{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T05:09:16Z","timestamp":1793423356173,"version":"4.5.0"},"reference-count":88,"publisher":"The Endocrine Society","issue":"5","license":[{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"vor","delay-in-days":9,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Programa de Apoyo a Proyectos de Investigaci\u00f3n e Innovaci\u00f3n Tecnol\u00f3gica (PAPIIT), UNAM, Mexico"},{"DOI":"10.13039\/501100006570","name":"Coordinaci\u00f3n de la Investigaci\u00f3n Cient\u00edfica (CIC), UNAM, Mexico","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006570","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Nanomaterials and Molecular Biophysics academic area of UAM-Lerma"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Mutations in the follicle-stimulating hormone receptor (FSHR) may result in impaired plasma membrane expression due to misfolding and intracellular retention of the receptor, leading to disease. Rescue of misfolded receptors may be achieved employing pharmacological chaperones (small molecules that specifically bind misfolded proteins, promoting their correct trafficking to their site of action). This study analyzed whether the small-molecule FSHR agonist CAN1405 rescued membrane expression and function of 13 mutant FSHRs leading to premature ovarian failure in women. FSHRs were expressed in HEK-293 cells, and membrane expression was assessed by immunoblotting before and after incubation with CAN1405. Three trafficking defective variants in the ectodomain of the FSHR (A189V, N191I, and D224V) and 3 others located in transmembrane domains (TMD) 3 and 4, and extracellular loop 2 (A462P, P504S, and P519T, respectively) failed to respond (or did it marginally) to CAN1405 by increasing their membrane expression. In contrast, in 7 variants located in the TMD2 (D408Y, A419T, and I423T), TMD6 (A575V, P587H, and F591S), and extracellular loop 3 (L597I), CAN1405 rescued membrane expression of the variants. Functional studies showed that after CAN1405 removal, rescued FSHRs responded to the orthosteric agonist in terms of cAMP-mediated signaling and ERK1\/2 phosphorylation. Refined molecular dynamics simulations using the cryo-EM structure of the FSHR revealed key conformational changes and interactions within the TMDs provoked by CAN1405, highlighting potential allosteric binding sites critical for receptor activation. These findings offer a promising therapeutic strategy for treating mutation-provoked FSHR dysfunction and underscore the synergistic potential of computational biophysics in drug discovery.<\/jats:p>","DOI":"10.1210\/endocr\/bqag045","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T11:34:55Z","timestamp":1776166495000},"source":"Crossref","is-referenced-by-count":1,"title":["Pharmacological rescue of follicle-stimulating hormone receptor mutants.\n                    <i>In vitro<\/i>\n                    and\n                    <i>in silico<\/i>\n                    studies"],"prefix":"10.1210","volume":"167","author":[{"given":"Teresa","family":"Zari\u00f1\u00e1n","sequence":"first","affiliation":[{"name":"Red de Apoyo a la Investigaci\u00f3n (RAI), National University of Mexico , Mexico City 04510 ,","place":["Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3701-429X","authenticated-orcid":false,"given":"Eduardo","family":"Jard\u00f3n-Valadez","sequence":"additional","affiliation":[{"name":"Departamento de Recursos de la Tierra, UAM-Unidad Lerma , Edo. de M\u00e9xico 52005 ,","place":["Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rub\u00e9n","family":"Guti\u00e9rrez-Sagal","sequence":"additional","affiliation":[{"name":"Red de Apoyo a la Investigaci\u00f3n (RAI), National University of Mexico , Mexico City 04510 ,","place":["Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0568-5929","authenticated-orcid":false,"given":"Ernesto","family":"Ulloa-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Selvaraj","family":"Nataraja","sequence":"additional","affiliation":[{"name":"Cancer Biology, Astellas Pharma , Cambridge, MA 02141 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry N","family":"Yu","sequence":"additional","affiliation":[{"name":"CanWell Pharma Inc. , Wellesley Hills, MA, 02481 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9532-3886","authenticated-orcid":false,"given":"Alfredo","family":"Ulloa-Aguirre","sequence":"additional","affiliation":[{"name":"Red de Apoyo a la Investigaci\u00f3n (RAI), National University of Mexico , Mexico City 04510 ,","place":["Mexico"]},{"name":"RAI, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n , Mexico City14000 ,","place":["Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2026,4,16]]},"reference":[{"issue":"4","key":"2026050522163467200_bqag045-B1","doi-asserted-by":"crossref","first-page":"468","DOI":"10.14310\/horm.2002.1632","article-title":"A short evolutionary history of FSH-stimulated spermatogenesis","volume":"14","author":"Huhtaniemi","year":"2015","journal-title":"Hormones (Athens)"},{"key":"2026050522163467200_bqag045-B2","first-page":"23","volume-title":"Yen & Jaffee\u00b4s Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management","author":"Narayan","year":"2024","edition":"9th ed."},{"issue":"4","key":"2026050522163467200_bqag045-B3","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1172\/JCI41350","article-title":"The ovary: basic biology and clinical implications","volume":"120","author":"Richards","year":"2010","journal-title":"J Clin Invest"},{"issue":"6","key":"2026050522163467200_bqag045-B4","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1124\/mol.63.6.1256","article-title":"The G-protein-coupled receptors in the human genome form five main families. 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