{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T04:28:01Z","timestamp":1787372881721,"version":"build-2736575974"},"reference-count":62,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Society for the Promotion of Science (JSPS) KAKENHI","award":["24K11186"],"award-info":[{"award-number":["24K11186"]}]},{"name":"Japan Society for the Promotion of Science (JSPS) KAKENHI","award":["22H04991"],"award-info":[{"award-number":["22H04991"]}]},{"DOI":"10.13039\/501100008664","name":"ONO Medical Research Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100008664","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>G protein-coupled receptors (GPCRs) are dynamic allosteric proteins whose signaling properties are governed by reciprocal communication between extracellular ligand-binding sites and intracellular transducer interfaces. Although classical pharmacological models established the concept that ligand binding and G protein coupling are thermodynamically linked, recent structural, biophysical, and computational studies have revealed a far more complex picture in which GPCRs exist as ensembles of interconverting conformational states. Accumulating evidence indicates that G proteins function not only as downstream signaling effectors but also as endogenous allosteric modulators. By reshaping receptor conformational landscapes, G protein coupling can influence the structure and dynamics of orthosteric ligand-binding pockets, thereby regulating ligand affinity, binding kinetics, and receptor selectivity. These findings support a bidirectional model of GPCR signaling in which information is transmitted not only from ligand-binding sites to intracellular signaling partners but also in the reverse direction through receptor-wide allosteric networks. Disease-associated mutations of endothelin A receptor (ETAR) provide in vivo evidence that structural perturbations located far from orthosteric ligand-binding sites can alter ligand recognition through long-range allosteric communication. In addition, emerging studies of positive allosteric modulators demonstrate the therapeutic potential of selectively stabilizing ligand\u2013receptor\u2013G protein complexes. These observations suggest that ligand recognition, receptor activation, and transducer coupling should be viewed as integrated properties of a dynamic receptor\u2013ligand\u2013transducer ensemble. This perspective provides a conceptual framework that links classical GPCR pharmacology, structural biology, disease mechanisms, and next-generation drug discovery.<\/jats:p>","DOI":"10.3390\/ph19081312","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T09:48:31Z","timestamp":1787219311000},"page":"1312","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["G Protein-Mediated Allosteric Modulation of Ligand Binding in Class A GPCRs: Receptor\u2013Ligand\u2013Transducer Ensembles in Disease and Drug Discovery"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7954-7433","authenticated-orcid":false,"given":"Yukiko","family":"Kurihara","sequence":"first","affiliation":[{"name":"Faculty of Nutrition Sciences, Japan Nutrition University, 3-9-21 Chiyoda, Sakado, Saitama 350-0288, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6476-5593","authenticated-orcid":false,"given":"Hiroki","family":"Kurihara","sequence":"additional","affiliation":[{"name":"Isotope Science Center, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan"},{"name":"Laboratory of Multicellular Dynamics, International Research Center for Medical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1146\/annurev-biochem-060614-033910","article-title":"The Molecular Basis of G Protein-Coupled Receptor Activation","volume":"87","author":"Weis","year":"2018","journal-title":"Annu. 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