7f4f

Cryo-EM structure of afamelanotide-bound melanocortin-1 receptor in complex with Gs protein and scFv16

Structural highlights

7f4f is a 6 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 2.9Å
Ligands:	CA, DPN, NLE
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

MSHR_HUMAN Familial melanoma;Oculocutaneous albinism type 2. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Function

C562_ECOLX Electron-transport protein of unknown function.MSHR_HUMAN Receptor for MSH (alpha, beta and gamma) and ACTH (PubMed:11442765, PubMed:11707265, PubMed:1325670, PubMed:1516719, PubMed:8463333). The activity of this receptor is mediated by G proteins which activate adenylate cyclase (PubMed:11707265, PubMed:1325670, PubMed:16463023, PubMed:19737927). Mediates melanogenesis, the production of eumelanin (black/brown) and phaeomelanin (red/yellow), via regulation of cAMP signaling in melanocytes (PubMed:31097585).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8]

Publication Abstract from PubMed

Melanocortins are peptide hormones critical for the regulation of stress response, energy homeostasis, inflammation, and skin pigmentation. Their functions are mediated by five G protein-coupled receptors (MC1R-MC5R), predominately through the stimulatory G protein (Gs). MC1R, the founding member of melanocortin receptors, is mainly expressed in melanocytes and is involved in melanogenesis. Dysfunction of MC1R is associated with the development of melanoma and skin cancer. Here we present three cryo-electron microscopy structures of the MC1R-Gs complexes bound to endogenous hormone alpha-MSH, a marketed drug afamelanotide, and a synthetic agonist SHU9119. These structures reveal the orthosteric binding pocket for the conserved HFRW motif among melanocortins and the crucial role of calcium ion in ligand binding. They also demonstrate the basis of differential activities among different ligands. In addition, unexpected interactions between MC1R and the Gbeta subunit were discovered from these structures. Together, our results elucidate a conserved mechanism of calcium-mediated ligand recognition, a specific mode of G protein coupling, and a universal activation pathway of melanocortin receptors.

Structural mechanism of calcium-mediated hormone recognition and Gbeta interaction by the human melanocortin-1 receptor.,Ma S, Chen Y, Dai A, Yin W, Guo J, Yang D, Zhou F, Jiang Y, Wang MW, Xu HE Cell Res. 2021 Oct;31(10):1061-1071. doi: 10.1038/s41422-021-00557-y. Epub 2021 , Aug 27. PMID:34453129^[9]

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

References

↑ Jiménez-Cervantes C, Olivares C, González P, Morandini R, Ghanem G, García-Borrón JC. The Pro162 variant is a loss-of-function mutation of the human melanocortin 1 receptor gene. J Invest Dermatol. 2001 Jul;117(1):156-8. PMID:11442765 doi:10.1046/j.0022-202x.2001.01393.x
↑ Jiménez-Cervantes C, Germer S, González P, Sánchez J, Sánchez CO, García-Borrón JC. Thr40 and Met122 are new partial loss-of-function natural mutations of the human melanocortin 1 receptor. FEBS Lett. 2001 Nov 9;508(1):44-8. PMID:11707265 doi:10.1016/s0014-5793(01)03025-3
↑ Mountjoy KG, Robbins LS, Mortrud MT, Cone RD. The cloning of a family of genes that encode the melanocortin receptors. Science. 1992 Aug 28;257(5074):1248-51. PMID:1325670 doi:10.1126/science.1325670
↑ Chhajlani V, Wikberg JE. Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA. FEBS Lett. 1992 Sep 14;309(3):417-20. PMID:1516719 doi:10.1016/0014-5793(92)80820-7
↑ Nakayama K, Soemantri A, Jin F, Dashnyam B, Ohtsuka R, Duanchang P, Isa MN, Settheetham-Ishida W, Harihara S, Ishida T. Identification of novel functional variants of the melanocortin 1 receptor gene originated from Asians. Hum Genet. 2006 Apr;119(3):322-30. PMID:16463023 doi:10.1007/s00439-006-0141-1
↑ Pérez-Oliva AB, Olivares C, Jiménez-Cervantes C, García-Borrón JC. Mahogunin ring finger-1 (MGRN1) E3 ubiquitin ligase inhibits signaling from melanocortin receptor by competition with Galphas. J Biol Chem. 2009 Nov 13;284(46):31714-25. PMID:19737927 doi:10.1074/jbc.M109.028100
↑ Ozdeslik RN, Olinski LE, Trieu MM, Oprian DD, Oancea E. Human nonvisual opsin 3 regulates pigmentation of epidermal melanocytes through functional interaction with melanocortin 1 receptor. Proc Natl Acad Sci U S A. 2019 Jun 4;116(23):11508-11517. PMID:31097585 doi:10.1073/pnas.1902825116
↑ Gantz I, Konda Y, Tashiro T, Shimoto Y, Miwa H, Munzert G, Watson SJ, DelValle J, Yamada T. Molecular cloning of a novel melanocortin receptor. J Biol Chem. 1993 Apr 15;268(11):8246-50 PMID:8463333
↑ Ma S, Chen Y, Dai A, Yin W, Guo J, Yang D, Zhou F, Jiang Y, Wang MW, Xu HE. Structural mechanism of calcium-mediated hormone recognition and Gβ interaction by the human melanocortin-1 receptor. Cell Res. 2021 Oct;31(10):1061-1071. PMID:34453129 doi:10.1038/s41422-021-00557-y

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Jiménez-Cervantes C, Olivares C, González P, Morandini R, Ghanem G, García-Borrón JC. The Pro162 variant is a loss-of-function mutation of the human melanocortin 1 receptor gene. J Invest Dermatol. 2001 Jul;117(1):156-8. PMID:11442765 doi:10.1046/j.0022-202x.2001.01393.x

[2] Jiménez-Cervantes C, Germer S, González P, Sánchez J, Sánchez CO, García-Borrón JC. Thr40 and Met122 are new partial loss-of-function natural mutations of the human melanocortin 1 receptor. FEBS Lett. 2001 Nov 9;508(1):44-8. PMID:11707265 doi:10.1016/s0014-5793(01)03025-3

[3] Mountjoy KG, Robbins LS, Mortrud MT, Cone RD. The cloning of a family of genes that encode the melanocortin receptors. Science. 1992 Aug 28;257(5074):1248-51. PMID:1325670 doi:10.1126/science.1325670

[4] Chhajlani V, Wikberg JE. Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA. FEBS Lett. 1992 Sep 14;309(3):417-20. PMID:1516719 doi:10.1016/0014-5793(92)80820-7

[5] Nakayama K, Soemantri A, Jin F, Dashnyam B, Ohtsuka R, Duanchang P, Isa MN, Settheetham-Ishida W, Harihara S, Ishida T. Identification of novel functional variants of the melanocortin 1 receptor gene originated from Asians. Hum Genet. 2006 Apr;119(3):322-30. PMID:16463023 doi:10.1007/s00439-006-0141-1

[6] Pérez-Oliva AB, Olivares C, Jiménez-Cervantes C, García-Borrón JC. Mahogunin ring finger-1 (MGRN1) E3 ubiquitin ligase inhibits signaling from melanocortin receptor by competition with Galphas. J Biol Chem. 2009 Nov 13;284(46):31714-25. PMID:19737927 doi:10.1074/jbc.M109.028100

[7] Ozdeslik RN, Olinski LE, Trieu MM, Oprian DD, Oancea E. Human nonvisual opsin 3 regulates pigmentation of epidermal melanocytes through functional interaction with melanocortin 1 receptor. Proc Natl Acad Sci U S A. 2019 Jun 4;116(23):11508-11517. PMID:31097585 doi:10.1073/pnas.1902825116

[8] Gantz I, Konda Y, Tashiro T, Shimoto Y, Miwa H, Munzert G, Watson SJ, DelValle J, Yamada T. Molecular cloning of a novel melanocortin receptor. J Biol Chem. 1993 Apr 15;268(11):8246-50 PMID:8463333

[9] Ma S, Chen Y, Dai A, Yin W, Guo J, Yang D, Zhou F, Jiang Y, Wang MW, Xu HE. Structural mechanism of calcium-mediated hormone recognition and Gβ interaction by the human melanocortin-1 receptor. Cell Res. 2021 Oct;31(10):1061-1071. PMID:34453129 doi:10.1038/s41422-021-00557-y

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7f4f

Cryo-EM structure of afamelanotide-bound melanocortin-1 receptor in complex with Gs protein and scFv16

Structural highlights

Disease

Function

Publication Abstract from PubMed

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References

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