期刊
PLOS BIOLOGY
卷 19, 期 6, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pbio.3001295
关键词
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资金
- Australian Research Council Centre grant [IC200100052]
- Australian Research Council DECRA grant [DE170100152]
- National Health and Medical Research Council Investigator Grant [APP1196951]
- National Health and Medical Research Council [APP1138448]
- National Health and Medical Research Council (of Australia) Program grant [1150083]
- National Health and Medical Research Council Senior Principal Research Fellow [1154434]
- National Health and Medical Research Council Senior Research Fellow [1155302]
- Australian Research Council Future Fellowship [FT180100543]
- Takeda Science Foundation
- Japan Science and Technology Agency PRESTO Grant [18069571]
- National Health and Medical Research Council of Australia [1154434, 1155302] Funding Source: NHMRC
- Australian Research Council [IC200100052, FT180100543, DE170100152] Funding Source: Australian Research Council
By studying the binding of cholecystokinin type 1 receptor to different G proteins, it was found that changes in receptor and G protein conformations play critical roles in the promiscuous coupling of individual GPCRs.
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-alpha 5 helix (alpha H5) 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 alpha H5 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.
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