{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:18:47Z","timestamp":1790644727457,"version":"4.1.0"},"reference-count":51,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,17]],"date-time":"2023-02-17T00:00:00Z","timestamp":1676592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea, funded by the Korean government","award":["NRF-2021R1A2C3003518"],"award-info":[{"award-number":["NRF-2021R1A2C3003518"]}]},{"name":"National Research Foundation of Korea, funded by the Korean government","award":["NRF-2019R1A5A2027340"],"award-info":[{"award-number":["NRF-2019R1A5A2027340"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Heterotrimeric guanine nucleotide-binding proteins (G proteins) are among the most important cellular signaling components, especially G protein-coupled receptors (GPCRs). G proteins comprise three subunits, G\u03b1, G\u03b2, and G\u03b3. G\u03b1 is the key subunit, and its structural state regulates the active status of G proteins. Interaction of guanosine diphosphate (GDP) or guanosine triphosphate (GTP) with G\u03b1 switches G protein into basal or active states, respectively. Genetic alteration in G\u03b1 could be responsible for the development of various diseases due to its critical role in cell signaling. Specifically, loss-of-function mutations of G\u03b1s are associated with parathyroid hormone-resistant syndrome such as inactivating parathyroid hormone\/parathyroid hormone-related peptide (PTH\/PTHrP) signaling disorders (iPPSDs), whereas gain-of-function mutations of G\u03b1s are associated with McCune\u2013Albright syndrome and tumor development. In the present study, we analyzed the structural and functional implications of natural variants of the G\u03b1s subtype observed in iPPSDs. Although a few tested natural variants did not alter the structure and function of G\u03b1s, others induced drastic conformational changes in G\u03b1s, resulting in improper folding and aggregation of the proteins. Other natural variants induced only mild conformational changes but altered the GDP\/GTP exchange kinetics. Therefore, the results shed light on the relationship between natural variants of G\u03b1 and iPPSDs.<\/jats:p>","DOI":"10.3390\/ijms24044064","type":"journal-article","created":{"date-parts":[[2023,2,20]],"date-time":"2023-02-20T03:56:07Z","timestamp":1676865367000},"page":"4064","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Structural and Functional Implication of Natural Variants of G\u03b1s"],"prefix":"10.3390","volume":"24","author":[{"given":"Yejin","family":"Jeong","sequence":"first","affiliation":[{"name":"School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9038-9571","authenticated-orcid":false,"given":"Ka Young","family":"Chung","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S46","DOI":"10.1038\/sj.bjp.0706405","article-title":"Heterotrimeric G-proteins: A short history","volume":"147","author":"Milligan","year":"2006","journal-title":"Br. 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