7f83

Crystal Structure of a receptor in Complex with inverse agonist

spinqualitylabelsall models 7f83, resolution 2.94Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7f83 is a 2 chain structure with sequence from Escherichia coli and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.94Å Ligands: 1KQ, OLC Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease GHSR_HUMAN Short stature due to GHSR deficiency. The disease is caused by variants affecting the gene represented in this entry. Function C562_ECOLX Electron-transport protein of unknown function.GHSR_HUMAN Receptor for ghrelin, coupled to G-alpha-11 proteins. Stimulates growth hormone secretion. Binds also other growth hormone releasing peptides (GHRP) (e.g. Met-enkephalin and GHRP-6) as well as non-peptide, low molecular weight secretagogues (e.g. L-692,429, MK-0677, adenosine). Publication Abstract from PubMed Much effort has been invested in the investigation of the structural basis of G protein-coupled receptors (GPCRs) activation. Inverse agonists, which can inhibit GPCRs with constitutive activity, are considered useful therapeutic agents, but the molecular mechanism of such ligands remains insufficiently understood. Here, we report a crystal structure of the ghrelin receptor bound to the inverse agonist PF-05190457 and a cryo-electron microscopy structure of the active ghrelin receptor-Go complex bound to the endogenous agonist ghrelin. Our structures reveal a distinct binding mode of the inverse agonist PF-05190457 in the ghrelin receptor, different from the binding mode of agonists and neutral antagonists. Combining the structural comparisons and cellular function assays, we find that a polar network and a notable hydrophobic cluster are required for receptor activation and constitutive activity. Together, our study provides insights into the detailed mechanism of ghrelin receptor binding to agonists and inverse agonists, and paves the way to design specific ligands targeting ghrelin receptors. Molecular mechanism of agonism and inverse agonism in ghrelin receptor.,Qin J, Cai Y, Xu Z, Ming Q, Ji SY, Wu C, Zhang H, Mao C, Shen DD, Hirata K, Ma Y, Yan W, Zhang Y, Shao Z Nat Commun. 2022 Jan 13;13(1):300. doi: 10.1038/s41467-022-27975-9. PMID:35027551 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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