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Publication Abstract from PubMed

G protein-coupled receptors (GPCRs) are critical regulators of cellular function acting via heterotrimeric G proteins as their primary transducers with individual GPCRs capable of pleiotropic coupling to multiple G proteins. Structural features governing G protein selectivity and promiscuity are currently unclear. Here, we used cryo-electron microscopy (cryo-EM) to determine structures of the cholecystokinin (CCK) type 1 receptor (CCK1R) bound to the CCK peptide agonist, CCK-8 and 2 distinct transducer proteins, its primary transducer Gq, and the more weakly coupled Gs. As seen with other Gq/11-GPCR complexes, the Gq-alpha5 helix (alphaH5) bound to a relatively narrow pocket in the CCK1R core. Surprisingly, the backbone of the CCK1R and volume of the G protein binding pocket were essentially equivalent when Gs was bound, with the Gs alphaH5 displaying a conformation that arises from "unwinding" of the far carboxyl-terminal residues, compared to canonically Gs coupled receptors. Thus, integrated changes in the conformations of both the receptor and G protein are likely to play critical roles in the promiscuous coupling of individual GPCRs.

Structures of the human cholecystokinin 1 (CCK1) receptor bound to Gs and Gq mimetic proteins provide insight into mechanisms of G protein selectivity.,Mobbs JI, Belousoff MJ, Harikumar KG, Piper SJ, Xu X, Furness SGB, Venugopal H, Christopoulos A, Danev R, Wootten D, Thal DM, Miller LJ, Sexton PM PLoS Biol. 2021 Jun 4;19(6):e3001295. doi: 10.1371/journal.pbio.3001295. , eCollection 2021 Jun. PMID:34086670^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.