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

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.

Source: ScienceNOW - April 22, 2020 Category: Science 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. Tags: Biochemistry reports Source Type: news