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Determination of the melanocortin-4 receptor structure identifies Ca 2+ as a cofactor for ligand binding.
- Source :
-
Science (New York, N.Y.) [Science] 2020 Apr 24; Vol. 368 (6489), pp. 428-433. - Publication Year :
- 2020
-
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 <superscript>2+</superscript> is identified as a cofactor that is complexed with residues from both the receptor and peptide ligand. Extracellular Ca <superscript>2+</superscript> 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.<br /> (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1095-9203
- Volume :
- 368
- Issue :
- 6489
- Database :
- MEDLINE
- Journal :
- Science (New York, N.Y.)
- Publication Type :
- Academic Journal
- Accession number :
- 32327598
- Full Text :
- https://doi.org/10.1126/science.aaz8995