1. Determination of the melanocortin-4 receptor structure identifies Ca 2+ as a cofactor for ligand binding.
- Author
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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, and Stevens RC
- Subjects
- Crystallography, X-Ray, Cyclic AMP chemistry, Humans, Ligands, Melanocyte-Stimulating Hormones chemistry, Melanocyte-Stimulating Hormones pharmacology, Mutation, Potassium Channels, Inwardly Rectifying chemistry, Protein Binding, Protein Multimerization, Protein Structure, Secondary, Receptor, Melanocortin, Type 4 antagonists & inhibitors, Receptor, Melanocortin, Type 4 genetics, Receptors, G-Protein-Coupled antagonists & inhibitors, Receptors, G-Protein-Coupled genetics, Signal Transduction, Calcium chemistry, Receptor, Melanocortin, Type 4 chemistry, Receptors, G-Protein-Coupled chemistry
- Abstract
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 Ca2+ increases the affinity and potency of the endogenous agonist α-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., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2020
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