8WKZ

Crystal structure of the Melanocortin-4 Receptor (MC4R) in complex with S31

Summary for 8WKZ

• Entry DOI: 10.2210/pdb8wkz/pdb
• Descriptor: Melanocortin receptor 4, [N-(3-{bis[2-(pyridin-2-yl-kappaN)ethyl]amino-kappaN}propyl)-5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide](azido)(hydroxy)copper, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: ca++ cofactor, gpcr, pgs fusion, membrane protein, lcp
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 62844.16

Authors

Gimenez, L.E.,Martin, C.,Yu, J.,Hollanders, C.,Hernandez, C.,Dahir, N.S.,Wu, Y.,Yao, D.,Han, G.W.,Wu, L.,Poorten, O.V.,Lamouroux, A.,Mannes, M.,Tourwe, D.,Zhao, S.,Stevens, R.C.,Cone, R.D.,Ballet, S. (deposition date: 2023-09-28, release date: 2024-08-07)

Primary citation

Gimenez, L.E.,Martin, C.,Yu, J.,Hollanders, C.,Hernandez, C.C.,Wu, Y.,Yao, D.,Han, G.W.,Dahir, N.S.,Wu, L.,Van der Poorten, O.,Lamouroux, A.,Mannes, M.,Zhao, S.,Tourwe, D.,Stevens, R.C.,Cone, R.D.,Ballet, S.
Novel Cocrystal Structures of Peptide Antagonists Bound to the Human Melanocortin Receptor 4 Unveil Unexplored Grounds for Structure-Based Drug Design.
J.Med.Chem., 67:2690-2711, 2024

PubMed Abstract: Melanocortin 4 receptor (MC4-R) antagonists are actively sought for treating cancer cachexia. We determined the structures of complexes with and . These peptides differ from by substituting His with Pro and inserting Gly or Arg. The structures revealed two subpockets at the TM7-TM1-TM2 domains, separated by N285. Two peptide series based on the complexed peptides led to an antagonist activity and selectivity SAR study. Most ligands retained the potency, but several -derived peptides significantly enhanced MC4-R selectivity over MC1-R by 60- to 132-fold. We also investigated MC4-R coupling to the K channel, Kir7.1. Some peptides activated the channel, whereas others induced channel closure independently of G protein coupling. In cell culture studies, channel activation correlated with increased feeding, while a peptide with Kir7.1 inhibitory activity reduced eating. These results highlight the potential for targeting the MC4-R:Kir7.1 complex for treating positive and restrictive eating disorders.

PubMed: 38345933
DOI: 10.1021/acs.jmedchem.3c01822

Experimental method

X-RAY DIFFRACTION (3.3 Å)