The Role of Intrinsically Disordered Domains in Regulating G Protein-Coupled Receptor Signaling. J Am Chem Soc 2026 Jan 14;148(1):1430-1443
Date
12/27/2025Pubmed ID
41454868Pubmed Central ID
PMC13050509DOI
10.1021/jacs.5c17796Scopus ID
2-s2.0-105027540729 (requires institutional sign-in at Scopus site) 3 CitationsAbstract
The α2A adrenergic receptor (α2AAR) is a clinically important target for various diseases including hypertension, diabetes, and chronic pain. Here, using single-molecule fluorescence resonance energy transfer imaging, we show how agonist-specific activation dynamics in both structured transmembrane domain (TMD) and intrinsic disorder regions (IDRs) of α2AAR lead to diverse signaling profiles. Through seven pairs of strategically designed fluorophore labels, we systematically investigate the real-time conformational changes of α2AAR. Our study reveals unique TM6 dynamics in α2AAR, featured by a high energy barrier for agonist-induced outward movements essential for activation. In contrast, we identify agonist-specific conformational dynamics of a partially disordered extracellular loop (ECL2), highlighting its role as a dynamic regulatory module that controls receptor function. Moreover, we characterize the conformational landscapes of the long third intracellular loop (ICL3), revealing its compact structural features and membrane-proximal localization in the basal state, where it acts as a negative allosteric regulator in transducer coupling. Furthermore, we identify multiple functional substates of ICL3 that are dynamically modulated by both kinase phosphorylation and drug efficacy. These findings offer previously underappreciated structural and dynamic insights into α2AAR function governed by both TMD and IDRs and may open up new avenues for the development of better therapeutics.
Author List
Xu J, Qiu R, Garces AM, Hübner H, Xu X, Hao C, Weikert D, Gmeiner P, Lerch MT, Kobilka BKAuthors
Alexander M. Garces Postdoctoral Researcher 1 in the Biophysics department at Medical College of WisconsinMichael Lerch PhD Associate Professor in the Biophysics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Fluorescence Resonance Energy TransferHumans
Intrinsically Disordered Proteins
Protein Domains
Receptors, Adrenergic, alpha-2
Signal Transduction
