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PDBsum entry 6w25
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Membrane protein
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PDB id
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6w25
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References listed in PDB file
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Key reference
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Title
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Determination of the melanocortin-4 receptor structure identifies ca2+ as a cofactor for ligand binding.
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Authors
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J.Yu,
L.E.Gimenez,
C.C.Hernandez,
Y.Wu,
A.H.Wein,
G.W.Han,
K.Mcclary,
S.R.Mittal,
K.Burdsall,
B.Stauch,
L.Wu,
S.N.Stevens,
A.Peisley,
S.Y.Williams,
V.Chen,
G.L.Millhauser,
S.Zhao,
R.D.Cone,
R.C.Stevens.
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Ref.
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Science, 2020,
368,
428-433.
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PubMed id
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Abstract
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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.
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