{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T22:08:25Z","timestamp":1790633305526,"version":"4.1.0"},"reference-count":19,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T00:00:00Z","timestamp":1691625600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University Grants Commission (UGC), University of Dhaka for Higher Education Quality Enhancement Project","award":["CP-4029"],"award-info":[{"award-number":["CP-4029"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>\n                    The disorder of thyroid gland development or thyroid dysgenesis accounts for 80\u201385% of congenital hypothyroidism (CH) cases. Mutations in the\n                    <jats:italic>TSHR<\/jats:italic>\n                    gene are mostly associated with thyroid dysgenesis, and prevent or disrupt normal development of the gland. There is limited data available on the genetic spectrum of congenital hypothyroid children in Bangladesh. Thus, an understanding of the molecular aetiology of thyroid dysgenesis is a prerequisite. The aim of the study was to investigate the effect of mutations in the\n                    <jats:italic>TSHR<\/jats:italic>\n                    gene on the small molecule thyrogenic drug-binding site of the protein. We identified two nonsynonymous mutations (p.Ser508Leu, p.Glu727Asp) in the exon 10 of the TSHR gene in 21 patients with dysgenesis by sequencing-based analysis. Later, the TSHR\n                    <jats:sub>368-764<\/jats:sub>\n                    protein was modeled by the I-TASSER server for wild-type and mutant structures. The model proteins were targeted by thyrogenic drugs, MS437 and MS438 to perceive the effect of mutations. The damaging effect in drug-protein complexes of mutants was explored by molecular docking and molecular dynamics simulations. The binding affinity of wild-type protein was much higher than the mutant cases for both of the drug ligands (MS437 and MS438). Molecular dynamics simulates the dynamic behavior of wild-type and mutant complexes. MS437-TSHR\n                    <jats:sub>368-764<\/jats:sub>\n                    MT2 and MS438-TSHR\n                    <jats:sub>368-764<\/jats:sub>\n                    MT1 showed stable conformations in biological environments. Finally, Principle Component Analysis revealed structural and energy profile discrepancies. TSHR\n                    <jats:sub>368-764<\/jats:sub>\n                    MT1 exhibited much more variations than TSHR\n                    <jats:sub>368-764<\/jats:sub>\n                    WT and TSHR\n                    <jats:sub>368-764<\/jats:sub>\n                    MT2, emphasizing a more damaging pattern in TSHR\n                    <jats:sub>368-764<\/jats:sub>\n                    MT1. This genetic study might be helpful to explore the mutational impact on drug binding sites of TSHR protein which is important for future drug design and selection for the treatment of congenital hypothyroid children with dysgenesis.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0282553","type":"journal-article","created":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T13:47:22Z","timestamp":1691675242000},"page":"e0282553","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Molecular investigation of TSHR gene in Bangladeshi congenital hypothyroid patients"],"prefix":"10.1371","volume":"18","author":[{"given":"Mst. Noorjahan","family":"Begum","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rumana","family":"Mahtarin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2822-245X","authenticated-orcid":true,"given":"Md. Tarikul","family":"Islam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sinthyia","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tasnia Kawsar","family":"Konika","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiissar","family":"Mannoor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharif","family":"Akhteruzzaman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8928-9888","authenticated-orcid":true,"given":"Firdausi","family":"Qadri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,8,10]]},"reference":[{"key":"pone.0282553.ref001","first-page":"2014","article-title":"Mat Junit SJBri. Functional analyses of c.","author":"CC Lee","year":"2014","journal-title":"2268dup in thyroid peroxidase gene associated with goitrous congenital hypothyroidism"},{"issue":"5\u20136","key":"pone.0282553.ref002","first-page":"419","article-title":"TSHR is the main causative locus in autosomal recessively inherited thyroid dysgenesis","volume":"25","author":"H Cangul","year":"2012","journal-title":"Journal of Pediatric Endocrinology and Metabolism"},{"issue":"2","key":"pone.0282553.ref003","first-page":"175","volume":"49","author":"A Kakinuma","year":"2002","journal-title":"Nagayama YJEj. 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Association"},{"key":"pone.0282553.ref007","doi-asserted-by":"crossref","first-page":"9218903","DOI":"10.1155\/2019\/9218903","article-title":"Mutation Spectrum in TPO Gene of Bangladeshi Patients with Thyroid Dyshormonogenesis and Analysis of the Effects of Different Mutations on the Structural Features and Functions of TPO Protein through In Silico Approach","volume":"2019","author":"MN Begum","year":"2019","journal-title":"BioMed research international"},{"issue":"W1","key":"pone.0282553.ref008","doi-asserted-by":"crossref","first-page":"W174","DOI":"10.1093\/nar\/gkv342","article-title":"I-TASSER server: new development for protein structure and function predictions","volume":"43","author":"J Yang","year":"2015","journal-title":"Nucleic Acids Res"},{"issue":"7","key":"pone.0282553.ref009","doi-asserted-by":"crossref","first-page":"2302","DOI":"10.1093\/nar\/gki524","article-title":"TM-align: a protein structure alignment algorithm based on the TM-score","volume":"33","author":"Y Zhang","year":"2005","journal-title":"Nucleic Acids Res"},{"key":"pone.0282553.ref010","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/978-1-4939-2269-7_19","article-title":"Small-molecule library screening by docking with PyRx","volume":"1263","author":"S Dallakyan","year":"2015","journal-title":"Methods in molecular biology"},{"issue":"23","key":"pone.0282553.ref011","doi-asserted-by":"crossref","first-page":"3676","DOI":"10.1093\/bioinformatics\/btw514","article-title":"PRODIGY: a web server for predicting the binding affinity of protein\u2013protein complexes","volume":"32","author":"LC Xue","year":"2016","journal-title":"Bioinformatics"},{"key":"pone.0282553.ref012","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/978-1-4939-7366-8_4","volume-title":"Protein Engineering: Methods and Protocols.","author":"H Land","year":"2018"},{"key":"pone.0282553.ref013","first-page":"1","author":"S Ahmed","year":"2021","journal-title":"Remdesivir analogs against SARS-CoV-2 RNA-dependent RNA polymerase"},{"issue":"16","key":"pone.0282553.ref014","first-page":"6290","article-title":"Investigating the binding affinity, interaction, and structure-activity-relationship of 76 prescription antiviral drugs targeting RdRp and Mpro of SARS-CoV-2.","volume":"39","author":"S Ahmed","year":"2021"},{"issue":"2","key":"pone.0282553.ref015","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1021\/acs.jproteome.0c00359","article-title":"Functions of Essential Genes and a Scale-Free Protein Interaction Network Revealed by Structure-Based Function and Interaction Prediction for a Minimal Genome","volume":"20","author":"C Zhang","year":"2021","journal-title":"Journal of Proteome Research"},{"key":"pone.0282553.ref016","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.sbi.2021.01.007","article-title":"Deep learning techniques have significantly impacted protein structure prediction and protein design","volume":"68","author":"R Pearce","year":"2021","journal-title":"Current opinion in structural biology"},{"issue":"7873","key":"pone.0282553.ref017","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"J Jumper","year":"2021","journal-title":"Nature"},{"issue":"7\u20138","key":"pone.0282553.ref018","first-page":"731","article-title":"A deletion including exon 2 of the TSHR gene is associated with thyroid dysgenesis and severe congenital hypothyroidism.","volume":"27","author":"H Cangul","year":"2014"},{"issue":"7","key":"pone.0282553.ref019","first-page":"2347","article-title":"Signaling\u2010sensitive amino acids surround the allosteric ligand binding site of the thyrotropin receptor.","volume":"24","author":"G Kleinau","year":"2010"}],"container-title":["PLOS 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