8ia7 › Citations

Structural insights into human brain-gut peptide cholecystokinin receptors.

<div class='caption-title'>Overall structures of CCK1R and CCK2R signaling complexes.</div>
<div class='caption-title'>Endogenous ligand recognition of CCK1R and CCK2R.</div>
<div class='caption-title'>Ligand selectivity of CCK1R for sulfated CCK.</div>
Ding Y, Zhang H, Liao YY, Chen LN, Ji SY, Qin J, Mao C, Shen DD, Lin L, Wang H, Zhang Y, Li XM
OpenAccess logo Cell Discov 8 55 (2022)
Related entries: 7xou, 7xov, 7xow

Cited: 2 times
EuropePMC logo PMID: 35672283

Abstract

The intestinal hormone and neuromodulator cholecystokinin (CCK) receptors CCK1R and CCK2R act as a signaling hub in brain-gut axis, mediating digestion, emotion, and memory regulation. CCK receptors exhibit distinct preferences for ligands in different posttranslational modification (PTM) states. CCK1R couples to Gs and Gq, whereas CCK2R primarily couples to Gq. Here we report the cryo-electron microscopy (cryo-EM) structures of CCK1R-Gs signaling complexes liganded either by sulfated cholecystokinin octapeptide (CCK-8) or a CCK1R-selective small-molecule SR146131, and CCK2R-Gq complexes stabilized by either sulfated CCK-8 or a CCK2R-selective ligand gastrin-17. Our structures reveal a location-conserved yet charge-distinct pocket discriminating the effects of ligand PTM states on receptor subtype preference, the unique pocket topology underlying selectivity of SR146131 and gastrin-17, the conformational changes in receptor activation, and key residues contributing to G protein subtype specificity, providing multiple structural templates for drug design targeting the brain-gut axis.

Articles citing this publication (2)

  1. A Novel CCK Receptor GPR173 Mediates Potentiation of GABAergic Inhibition. He L, Shi H, Zhang G, Peng Y, Ghosh A, Zhang M, Hu X, Liu C, Shao Y, Wang S, Chen L, Sun W, Su J, Chen X, Zhang L, Chan YS, Pei D, Tortorella M, Guo Y, Yan H, He J. J Neurosci 43 2305-2325 (2023)
  2. Elucidating the molecular determinants in the process of gastrin C-terminal pentapeptide amide end activating cholecystokinin 2 receptor by Gaussian accelerated molecular dynamics simulations. Yang K, Jin H, Gao X, Wang GC, Zhang GQ. Front Pharmacol 13 1054575 (2022)


Quick links