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TitleStructures of the human cholecystokinin 1 (CCK1) receptor bound to Gs and Gq mimetic proteins provide insight into mechanisms of G protein selectivity.
Journal, issue, pagesPLoS Biol, Vol. 19, Issue 6, Page e3001295, Year 2021
Publish dateJun 4, 2021
AuthorsJesse I Mobbs / Matthew J Belousoff / Kaleeckal G Harikumar / Sarah J Piper / Xiaomeng Xu / Sebastian G B Furness / Hari Venugopal / Arthur Christopoulos / Radostin Danev / Denise Wootten / David M Thal / Laurence J Miller / Patrick M Sexton /
PubMed AbstractG 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 ...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-α5 helix (αH5) 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 αH5 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.
External linksPLoS Biol / PubMed:34086670 / PubMed Central
MethodsEM (single particle)
Resolution1.95 - 2.44 Å
Structure data

EMDB-23749, PDB-7mbx:
Human Cholecystokinin 1 receptor (CCK1R) Gs complex
Method: EM (single particle) / Resolution: 1.95 Å

EMDB-23750, PDB-7mby:
Human Cholecystokinin 1 receptor (CCK1R) Gq chimera (mGsqi) complex
Method: EM (single particle) / Resolution: 2.44 Å

Chemicals

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-HOH:
WATER / Water

Source
  • homo sapiens (human)
  • rattus norvegicus (Norway rat)
  • lama glama (llama)
  • Mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN/SIGNALING PROTEIN / GPCR / MEMBRANE PROTEIN / MEMBRANE PROTEIN-SIGNALING PROTEIN complex

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