| Structural highlights
6w25 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , |
| NonStd Res: | , , , , |
| Gene: | MC4R (HUMAN) |
| 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
The melanocortin-4 receptor (MC4R) is involved in energy homeostasis and is an important drug target for syndromic obesity. We report the structure of the antagonist SHU9119-bound human MC4R at 2.8-angstrom resolution. Ca(2+) is identified as a cofactor that is complexed with residues from both the receptor and peptide ligand. Extracellular Ca(2+) increases the affinity and potency of the endogenous agonist alpha-melanocyte-stimulating hormone at the MC4R by 37- and 600-fold, respectively. The ability of the MC4R crystallized construct to couple to ion channel Kir7.1, while lacking cyclic adenosine monophosphate stimulation, highlights a heterotrimeric GTP-binding protein (G protein)-independent mechanism for this signaling modality. MC4R is revealed as a structurally divergent G protein-coupled receptor (GPCR), with more similarity to lipidic GPCRs than to the homologous peptidic GPCRs.
Determination of the melanocortin-4 receptor structure identifies Ca(2+) as a cofactor for ligand binding.,Yu J, Gimenez LE, Hernandez CC, Wu Y, Wein AH, Han GW, McClary K, Mittal SR, Burdsall K, Stauch B, Wu L, Stevens SN, Peisley A, Williams SY, Chen V, Millhauser GL, Zhao S, Cone RD, Stevens RC Science. 2020 Apr 24;368(6489):428-433. doi: 10.1126/science.aaz8995. PMID:32327598[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
- ↑ Yu J, Gimenez LE, Hernandez CC, Wu Y, Wein AH, Han GW, McClary K, Mittal SR, Burdsall K, Stauch B, Wu L, Stevens SN, Peisley A, Williams SY, Chen V, Millhauser GL, Zhao S, Cone RD, Stevens RC. Determination of the melanocortin-4 receptor structure identifies Ca(2+) as a cofactor for ligand binding. Science. 2020 Apr 24;368(6489):428-433. doi: 10.1126/science.aaz8995. PMID:32327598 doi:http://dx.doi.org/10.1126/science.aaz8995
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