7aue

Melanocortin receptor 4 (MC4R) Gs protein complexMelanocortin receptor 4 (MC4R) Gs protein complex

Structural highlights

7aue is a 6 chain structure with sequence from Homo sapiens, Mus musculus and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , ,
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

Obesity is a global epidemic that causes morbidity and impaired quality of life. The melanocortin receptor 4 (MC4R) is at the crux of appetite, energy homeostasis, and body-weight control in the central nervous system and is a prime target for anti-obesity drugs. Here, we present the cryo-electron microscopy (cryo-EM) structure of the human MC4R-G(s) signaling complex bound to the agonist setmelanotide, a cyclic peptide recently approved for the treatment of obesity. The work reveals the mechanism of MC4R activation, highlighting a molecular switch that initiates satiation signaling. In addition, our findings indicate that calcium (Ca(2+)) is required for agonist, but not antagonist, efficacy. These results fill a gap in the understanding of MC4R activation and could guide the design of future weight-management drugs.

Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling.,Israeli H, Degtjarik O, Fierro F, Chunilal V, Gill AK, Roth NJ, Botta J, Prabahar V, Peleg Y, Chan LF, Ben-Zvi D, McCormick PJ, Niv MY, Shalev-Benami M Science. 2021 May 21;372(6544):808-814. doi: 10.1126/science.abf7958. Epub 2021 , Apr 15. PMID:33858992^[3]

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

References

↑ 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
↑ 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
↑ Israeli H, Degtjarik O, Fierro F, Chunilal V, Gill AK, Roth NJ, Botta J, Prabahar V, Peleg Y, Chan LF, Ben-Zvi D, McCormick PJ, Niv MY, Shalev-Benami M. Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling. Science. 2021 May 21;372(6544):808-814. PMID:33858992 doi:10.1126/science.abf7958

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

[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] Israeli H, Degtjarik O, Fierro F, Chunilal V, Gill AK, Roth NJ, Botta J, Prabahar V, Peleg Y, Chan LF, Ben-Zvi D, McCormick PJ, Niv MY, Shalev-Benami M. Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling. Science. 2021 May 21;372(6544):808-814. PMID:33858992 doi:10.1126/science.abf7958

[1]

[2]

[3]