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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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PDB id:
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| Name: |
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Signaling protein
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Title:
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Crystal structure of the extracellular domain of human calcium sensing receptor
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Structure:
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Extracellular calcium-sensing receptor. Chain: a, b. Fragment: unp residues 20-541. Synonym: casr,parathyroid cell calcium-sensing receptor 1,pcar1. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: casr, gprc2a, pcar1. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek293
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Resolution:
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2.10Å
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R-factor:
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0.191
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R-free:
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0.223
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Authors:
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T.Zhang,C.Zhang,C.L.Miller,J.Zou,K.W.Moremen,E.M.Brown,J.J.Yang,J.Hu
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Key ref:
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C.Zhang
et al.
(2016).
Structural basis for regulation of human calcium-sensing receptor by magnesium ions and an unexpected tryptophan derivative co-agonist.
Sci Adv,
2,
e1600241.
PubMed id:
DOI:
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Date:
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14-Dec-15
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Release date:
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22-Jun-16
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PROCHECK
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Headers
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References
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P41180
(CASR_HUMAN) -
Extracellular calcium-sensing receptor from Homo sapiens
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Seq:
Struc:
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1078 a.a.
487 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 2 residue positions (black
crosses)
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DOI no:
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Sci Adv
2:e1600241
(2016)
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PubMed id:
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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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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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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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