6W25

Crystal structure of the Melanocortin-4 Receptor (MC4R) in complex with SHU9119

Summary for 6W25

• Entry DOI: 10.2210/pdb6w25/pdb
• Descriptor: Melanocortin receptor 4,GlgA glycogen synthase,Melanocortin receptor 4, SHU9119, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: melanocortin-4 receptor, ca++ cofactor, shu9119, gpcr, pgs fusion, membrane protein, lcp
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 63575.38

Authors

Yu, J.,Gimenez, L.E.,Hernandez, C.C.,Wu, Y.,Wein, A.H.,Han, G.W.,McClary, K.,Mittal, S.R.,Burdsall, K.,Stauch, B.,Wu, L.,Stevens, S.N.,Peisley, A.,Williams, S.Y.,Chen, V.,Millhauser, G.L.,Zhao, S.,Cone, R.D.,Stevens, R.C. (deposition date: 2020-03-04, release date: 2020-04-29, Last modification date: 2023-11-15)

Primary citation

Yu, J.,Gimenez, L.E.,Hernandez, C.C.,Wu, Y.,Wein, A.H.,Han, G.W.,McClary, K.,Mittal, S.R.,Burdsall, K.,Stauch, B.,Wu, L.,Stevens, S.N.,Peisley, A.,Williams, S.Y.,Chen, V.,Millhauser, G.L.,Zhao, S.,Cone, R.D.,Stevens, R.C.
Determination of the melanocortin-4 receptor structure identifies Ca2+as a cofactor for ligand binding.
Science, 368:428-433, 2020

PubMed 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 is identified as a cofactor that is complexed with residues from both the receptor and peptide ligand. Extracellular Ca 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.

PubMed: 32327598
DOI: 10.1126/science.aaz8995

Experimental method

X-RAY DIFFRACTION (2.75 Å)