{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:03:08Z","timestamp":1792803788587,"version":"4.5.0"},"reference-count":59,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T00:00:00Z","timestamp":1671667200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Macao Polytechnic University","award":["RP\/CAI-01\/2022"],"award-info":[{"award-number":["RP\/CAI-01\/2022"]}],"id":[{"id":"https:\/\/ror.org\/02sf5td35","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Macao Polytechnic University","award":["82160676"],"award-info":[{"award-number":["82160676"]}],"id":[{"id":"https:\/\/ror.org\/02sf5td35","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Macao Polytechnic University","award":["KYCX21_0568"],"award-info":[{"award-number":["KYCX21_0568"]}],"id":[{"id":"https:\/\/ror.org\/02sf5td35","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["RP\/CAI-01\/2022"],"award-info":[{"award-number":["RP\/CAI-01\/2022"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82160676"],"award-info":[{"award-number":["82160676"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["KYCX21_0568"],"award-info":[{"award-number":["KYCX21_0568"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"ostgraduate Research &amp; Practice Innovation Program of Jiangsu Province","award":["RP\/CAI-01\/2022"],"award-info":[{"award-number":["RP\/CAI-01\/2022"]}]},{"name":"ostgraduate Research &amp; Practice Innovation Program of Jiangsu Province","award":["82160676"],"award-info":[{"award-number":["82160676"]}]},{"name":"ostgraduate Research &amp; Practice Innovation Program of Jiangsu Province","award":["KYCX21_0568"],"award-info":[{"award-number":["KYCX21_0568"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The parathyroid hormone type 1 receptor (PTH1R) acts as a canonical class B G protein-coupled receptor, regulating crucial functions including calcium homeostasis and bone formation. The identification and development of PTH1R non-peptide allosteric modulators have obtained widespread attention. It has been found that a negative allosteric modulator (NAM) could inhibit the activation of PTH1R, but the implied mechanism remains unclear. Herein, extensive molecular dynamics simulations together with multiple analytical approaches are utilized to unravel the mechanism of PTH1R allosteric inhibition. The results suggest that the binding of NAM destabilizes the structure of the PTH1R\u2013PTH\u2013spep\/qpep (the C terminus of Gs\/Gq proteins) complexes. Moreover, the presence of NAM weakens the binding of PTH\/peps (spep and qpep) and PTH1R. The intra- and inter-molecular couplings are also weakened in PTH1R upon NAM binding. Interestingly, compared with our previous study of the positive allosteric effects induced by extracellular Ca2+, the enhanced correlation between the PTH and G-protein binding sites is significantly reduced by the replacement of this negative allosteric regulator. Our findings might contribute to the development of new therapeutic agents for diseases caused by the abnormal activation of PTH1R.<\/jats:p>","DOI":"10.3390\/cells12010041","type":"journal-article","created":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T03:02:15Z","timestamp":1671764535000},"page":"41","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Understanding the Allosteric Modulation of PTH1R by a Negative Allosteric Modulator"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0014-5683","authenticated-orcid":false,"given":"Mengrong","family":"Li","sequence":"first","affiliation":[{"name":"College of Life Sciences, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8835-0587","authenticated-orcid":false,"given":"Yiqiong","family":"Bao","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Xu","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaomiao","family":"Li","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Xi","sequence":"additional","affiliation":[{"name":"Office of Institution of Drug Clinical Trial, The First Hospital of Lanzhou University, Lanzhou 730000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4632-4364","authenticated-orcid":false,"given":"Jingjing","family":"Guo","sequence":"additional","affiliation":[{"name":"Centre in Artificial Intelligence Driven Drug Discovery, Faculty of Applied Science, Macao Polytechnic University, Macao 999078, China"},{"name":"Engineering Research Centre of Applied Technology on Machine Translation and Artificial Intelligence, Macao Polytechnic University, Macao 999078, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1038\/nrd3702","article-title":"Neuropeptide receptor ligands as drugs for psychiatric diseases: The end of the beginning?","volume":"11","author":"Griebel","year":"2012","journal-title":"Nat. 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