Structural basis for regulation of human calcium-sensing receptor by magnesium ions and an unexpected tryptophan derivative co-agonist

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(...

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Bibliographic Details
Published in:Science advances 2016-05, Vol.2 (5), p.e1600241-e1600241
Main Authors: Zhang, Chen, Zhang, Tuo, Zou, Juan, Miller, Cassandra Lynn, Gorkhali, Rakshya, Yang, Jeong-Yeh, Schilmiller, Anthony, Wang, Shuo, Huang, Kenneth, Brown, Edward M, Moremen, Kelley W, Hu, Jian, Yang, Jenny J
Format: Article
Language:English
Subjects:
Binding Affinity
Biochemistry
Calcium Sensing Receptor
Cell Line
Crystal Structure
EC50
Humans
Ions - chemistry
Ions - metabolism
L-Phe
Ligands
Magnesium - chemistry
Magnesium - metabolism
Mg2
Models, Molecular
Molecular Conformation
Mutation
Protein Binding
Receptors, Calcium-Sensing - agonists
Receptors, Calcium-Sensing - chemistry
Receptors, Calcium-Sensing - genetics
Receptors, Calcium-Sensing - metabolism
SciAdv r-articles
Structure-Activity Relationship
TNCA
Tryptophan - analogs & derivatives
Tryptophan - chemistry
Tryptophan - metabolism
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Summary: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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.1600241