Determination of the melanocortin-4 receptor structure identifies Ca2+ as a cofactor for ligand binding

  • Science. 2020 Apr 24;368(6489):428-433. doi: 10.1126/science.aaz8995.
Jing Yu  1  2  3 ,  Luis E Gimenez  4 ,  Ciria C Hernandez  4 ,  Yiran Wu  1 ,  Ariel H Wein  5 ,  Gye Won Han  5 ,  Kyle McClary  5 ,  Sanraj R Mittal  5 ,  Kylie Burdsall  5 ,  Benjamin Stauch  5 ,  Lijie Wu  1 ,  Sophia N Stevens  1 ,  Alys Peisley  4 ,  Savannah Y Williams  4 ,  Valerie Chen  6 ,  Glenn L Millhauser  6 ,  Suwen Zhao  1  2 ,  Roger D Cone  7  8 ,  Raymond C Stevens  9  2  5
Affiliations
  • 1. iHuman Institute, ShanghaiTech University, Pudong, Shanghai 201210, China.
  • 2. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 3. CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai 200031, China.
  • 4. Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
  • 5. Departments of Biological Sciences and Chemistry, Bridge Institute, USC Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA 90089, USA.
  • 6. Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95064, USA.
  • 7. Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA. [email protected] [email protected].
  • 8. Department of Molecular and Integrative Physiology, School of Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • 9. iHuman Institute, ShanghaiTech University, Pudong, Shanghai 201210, China. [email protected] [email protected].
PMID: 32327598 DOI: 10.1126/science.aaz8995
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. CA2+ 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.