7f58

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Cryo-EM structure of THIQ-MC4R-Gs_Nb35 complex

Structural highlights

7f58 is a 5 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 3.1Å
Ligands:1I8, CA
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

MC4R_HUMAN Obesity due to melanocortin 4 receptor deficiency. The disease is caused by mutations affecting the gene represented in this entry.

Function

MC4R_HUMAN Receptor specific to the heptapeptide core common to adrenocorticotropic hormone and alpha-, beta-, and gamma-MSH. Plays a central role in energy homeostasis and somatic growth. This receptor is mediated by G proteins that stimulate adenylate cyclase (cAMP).[1] [2]

Publication Abstract from PubMed

Melanocortin-4 receptor (MC4R) plays a central role in the regulation of energy homeostasis. Its high sequence similarity to other MC receptor family members, low agonist selectivity and the lack of structural information concerning MC4R-specific activation have hampered the development of MC4R-seletive therapeutics to treat obesity. Here, we report four high-resolution structures of full-length MC4R in complex with the heterotrimeric G(s) protein stimulated by the endogenous peptide ligand alpha-MSH, FDA-approved drugs afamelanotide (Scenesse) and bremelanotide (Vyleesi), and a selective small-molecule ligand THIQ, respectively. Together with pharmacological studies, our results reveal the conserved binding mode of peptidic agonists, the distinctive molecular details of small-molecule agonist recognition underlying receptor subtype selectivity, and a distinct activation mechanism for MC4R, thereby offering new insights into G protein coupling. Our work may facilitate the discovery of selective therapeutic agents targeting MC4R.

Structural insights into ligand recognition and activation of the melanocortin-4 receptor.,Zhang H, Chen LN, Yang D, Mao C, Shen Q, Feng W, Shen DD, Dai A, Xie S, Zhou Y, Qin J, Sun JP, Scharf DH, Hou T, Zhou T, Wang MW, Zhang Y Cell Res. 2021 Nov;31(11):1163-1175. doi: 10.1038/s41422-021-00552-3. Epub 2021 , Aug 25. PMID:34433901[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
1 reviews cite this structure
Lipocalin 2 receptors: facts, fictions, and myths.
Schröder et al. (2023)
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14 other articles
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See Also

References

  1. ↑ Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O'Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med. 2003 Mar 20;348(12):1085-95. PMID:12646665 doi:http://dx.doi.org/10.1056/NEJMoa022050
  2. ↑ Delhanty PJ, Bouw E, Huisman M, Vervenne RM, Themmen AP, van der Lely AJ, van den Akker EL. Functional characterization of a new human melanocortin-4 receptor homozygous mutation (N72K) that is associated with early-onset obesity. Mol Biol Rep. 2014 Dec;41(12):7967-72. doi: 10.1007/s11033-014-3691-7. Epub 2014 , Aug 28. PMID:25163632 doi:http://dx.doi.org/10.1007/s11033-014-3691-7
  3. ↑ Zhang H, Chen LN, Yang D, Mao C, Shen Q, Feng W, Shen DD, Dai A, Xie S, Zhou Y, Qin J, Sun JP, Scharf DH, Hou T, Zhou T, Wang MW, Zhang Y. Structural insights into ligand recognition and activation of the melanocortin-4 receptor. Cell Res. 2021 Nov;31(11):1163-1175. PMID:34433901 doi:10.1038/s41422-021-00552-3

Contents


PDB ID 7f58

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OCA

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