7XOU

Structural insights into human brain gut peptide cholecystokinin receptors

Summary for 7XOU

• Entry DOI: 10.2210/pdb7xou/pdb
• EMDB information: 33359
• Descriptor: CCK-8, Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (6 entities in total)
• Functional Keywords: brain gut peptide receptor class a g-protein-coupled receptor, neuropeptide
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 156614.41

Authors

Ding, Y.,Zhang, H.,Liao, Y.,Chen, L.,Ji, S. (deposition date: 2022-05-01, release date: 2022-07-20)

Primary citation

Ding, Y.,Zhang, H.,Liao, Y.Y.,Chen, L.N.,Ji, S.Y.,Qin, J.,Mao, C.,Shen, D.D.,Lin, L.,Wang, H.,Zhang, Y.,Li, X.M.
Structural insights into human brain-gut peptide cholecystokinin receptors.
Cell Discov, 8:55-55, 2022

PubMed 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 G and G, whereas CCK2R primarily couples to G. Here we report the cryo-electron microscopy (cryo-EM) structures of CCK1R-G signaling complexes liganded either by sulfated cholecystokinin octapeptide (CCK-8) or a CCK1R-selective small-molecule SR146131, and CCK2R-G 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.

PubMed: 35672283
DOI: 10.1038/s41421-022-00420-3

Experimental method

ELECTRON MICROSCOPY (3.2 Å)