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PDBsum entry 5fbk
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Signaling protein
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PDB id
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5fbk
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References listed in PDB file
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Key reference
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Title
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Structural basis for regulation of human calcium-Sensing receptor by magnesium ions and an unexpected tryptophan derivative co-Agonist.
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Authors
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C.Zhang,
T.Zhang,
J.Zou,
C.L.Miller,
R.Gorkhali,
J.Y.Yang,
A.Schilmiller,
S.Wang,
K.Huang,
E.M.Brown,
K.W.Moremen,
J.Hu,
J.J.Yang.
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Ref.
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Sci Adv, 2016,
2,
e1600241.
[DOI no: ]
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PubMed id
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Abstract
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Ca(2+)-sensing receptors (CaSRs) modulate calcium and magnesium homeostasis and
many (patho)physiological processes by responding to extracellular stimuli,
including divalent cations and amino acids. We report the first crystal
structure of the extracellular domain (ECD) of human CaSR bound with Mg(2+) and
a tryptophan derivative ligand at 2.1 Å. The structure reveals key determinants
for cooperative activation by metal ions and aromatic amino acids. The
unexpected tryptophan derivative was bound in the hinge region between two
globular ECD subdomains, and represents a novel high-affinity co-agonist of
CaSR. The dissection of structure-function relations by mutagenesis,
biochemical, and functional studies provides insights into the molecular basis
of human diseases arising from CaSR mutations. The data also provide a novel
paradigm for understanding the mechanism of CaSR-mediated signaling that is
likely shared by the other family C GPCR [G protein (heterotrimeric guanine
nucleotide-binding protein)-coupled receptor] members and can facilitate the
development of novel CaSR-based therapeutics.
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