9bkk

Cholecystokinin 1 receptor (CCK1R) sterol 7M mutant, Gq chimera (mGsqi) complex

spinqualitylabelsall models 9bkk, resolution 2.51Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9bkk is a 5 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.51Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CCKN_HUMAN This peptide hormone induces gall bladder contraction and the release of pancreatic enzymes in the gut. Its function in the brain is not clear. Binding to CCK-A receptors stimulates amylase release from the pancreas, binding to CCK-B receptors stimulates gastric acid secretion.[UniProtKB:Q9TS44] Publication Abstract from PubMed Development of optimal therapeutics for disease states that can be associated with increased membrane cholesterol requires better molecular understanding of lipid modulation of the drug target. Type 1 cholecystokinin receptor (CCK1R) agonist actions are affected by increased membrane cholesterol, enhancing ligand binding and reducing calcium signaling, while agonist actions of the closely related CCK2R are not. In this work, we identified a set of chimeric human CCK1R/CCK2R mutations that exchange the cholesterol sensitivity of these 2 receptors, providing powerful tools when expressed in CHO and HEK-293 model cell lines to explore mechanisms. Static, low energy, high-resolution structures of the mutant CCK1R constructs, stabilized in complex with G protein, were not substantially different, suggesting that alterations to receptor dynamics were key to altered function. We reveal that cholesterol-dependent dynamic changes in the conformation of the helical bundle of CCK receptors affects both ligand binding at the extracellular surface and G protein coupling at the cytosolic surface, as well as their interrelationships involved in stimulus-response coupling. This provides an ideal setting for potential allosteric modulators to correct the negative impact of membrane cholesterol on CCK1R. Cholesterol-dependent dynamic changes in the conformation of the type 1 cholecystokinin receptor affect ligand binding and G protein coupling.,Harikumar KG, Zhao P, Cary BP, Xu X, Desai AJ, Dong M, Mobbs JI, Toufaily C, Furness SGB, Christopoulos A, Belousoff MJ, Wootten D, Sexton PM, Miller LJ PLoS Biol. 2024 Jul 31;22(7):e3002673. doi: 10.1371/journal.pbio.3002673. , eCollection 2024 Jul. PMID:39083706 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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