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Structure and function of the human calcium-sensing receptor: insights from natural and engineered mutations and allosteric modulators.

Hu J, Spiegel AM - J. Cell. Mol. Med. (2007 Sep-Oct)

Bottom Line: The human extracellular Ca(2+)-sensing receptor (CaR), a member of the G protein-coupled receptor family 3, plays a key role in the regulation of extracellular calcium homeostasis.It is one of just a few G protein-coupled receptors with a large number of naturally occurring mutations identified in patients.In contrast to the small sizes of its agonists, this large dimeric receptor consists of domains with topologically distinctive orthosteric and allosteric sites.

View Article: PubMed Central - PubMed

Affiliation: Molecular Signalling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. jianxinh@niddk.nih.gov

ABSTRACT
The human extracellular Ca(2+)-sensing receptor (CaR), a member of the G protein-coupled receptor family 3, plays a key role in the regulation of extracellular calcium homeostasis. It is one of just a few G protein-coupled receptors with a large number of naturally occurring mutations identified in patients. In contrast to the small sizes of its agonists, this large dimeric receptor consists of domains with topologically distinctive orthosteric and allosteric sites. Information derived from studies of naturally occurring mutations, engineered mutations, allosteric modulators and crystal structures of the agonist-binding domain of homologous type 1 metabotropic glutamate receptor and G protein-coupled rhodopsin offers new insights into the structure and function of the CaR.

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Schematic representation of the CaR 7TM. Molecular docking results indicated two potential binding pockets for allosteric modulators within the upper part of the transmembrane helical bundle. The red circle indicates pocket P1, enclosed within TM3 (green), TM4 (purple), TM5 (blue), TM6 (brown) and exo-loop2; the blue circle indicates pocket P2, enclosed within TM1 (cyan), TM2 (orange), TM3, TM6, TM7 (yellow-green) and exo-loop 2. Residues E767, E837, and the conserved disulphide bond (C677–C765) connecting exo-loop 1 and 2 are shown as Corey-Pauling-Koltun. Compound 1 and its analogue JKJ05 are proposed to bind to pocket P1. JKJ05 is a negative modulator of the wild-type CaR and a positive modulator of E837A mutant CaR, and the positive modulation critically depends on the primary amine in JKJ05 which appears to interact with residue E767 in this model. Phenylalkylamines structurally related to NPS R-568 are proposed to bind to pocket P2, and they anchor to the pocket through a critical salt bridge between their positively charged central amino group and the acidic residue E837 in TM7.
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fig03: Schematic representation of the CaR 7TM. Molecular docking results indicated two potential binding pockets for allosteric modulators within the upper part of the transmembrane helical bundle. The red circle indicates pocket P1, enclosed within TM3 (green), TM4 (purple), TM5 (blue), TM6 (brown) and exo-loop2; the blue circle indicates pocket P2, enclosed within TM1 (cyan), TM2 (orange), TM3, TM6, TM7 (yellow-green) and exo-loop 2. Residues E767, E837, and the conserved disulphide bond (C677–C765) connecting exo-loop 1 and 2 are shown as Corey-Pauling-Koltun. Compound 1 and its analogue JKJ05 are proposed to bind to pocket P1. JKJ05 is a negative modulator of the wild-type CaR and a positive modulator of E837A mutant CaR, and the positive modulation critically depends on the primary amine in JKJ05 which appears to interact with residue E767 in this model. Phenylalkylamines structurally related to NPS R-568 are proposed to bind to pocket P2, and they anchor to the pocket through a critical salt bridge between their positively charged central amino group and the acidic residue E837 in TM7.

Mentions: Negative modulators of the CaR, so-called calcilytic drugs such as NPS2143 [75], NPS89636 [76], Calhex-231 [42], Compound 1 [77] and certain derivatives of NPS2143 [78, 79] block Ca2+ activation of the CaR. These compounds, except Compound 1, are phenylalkylamines structurally related to those type II calcimimetics demonstrating that subtle differences in the configuration of compounds binding to the CaR 7TM might either prevent (negative modulators) or promote (positive modulators) helical motion required for receptor activation. Negative modulation of the CaR by NPS2143 and Calhex-231 also critically depend on residue E837 located in the TM7 (Fig. 3) [42, 43]. Both compounds are primarily anchored through an H-bond assisted salt bridge to this negatively charged residue.


Structure and function of the human calcium-sensing receptor: insights from natural and engineered mutations and allosteric modulators.

Hu J, Spiegel AM - J. Cell. Mol. Med. (2007 Sep-Oct)

Schematic representation of the CaR 7TM. Molecular docking results indicated two potential binding pockets for allosteric modulators within the upper part of the transmembrane helical bundle. The red circle indicates pocket P1, enclosed within TM3 (green), TM4 (purple), TM5 (blue), TM6 (brown) and exo-loop2; the blue circle indicates pocket P2, enclosed within TM1 (cyan), TM2 (orange), TM3, TM6, TM7 (yellow-green) and exo-loop 2. Residues E767, E837, and the conserved disulphide bond (C677–C765) connecting exo-loop 1 and 2 are shown as Corey-Pauling-Koltun. Compound 1 and its analogue JKJ05 are proposed to bind to pocket P1. JKJ05 is a negative modulator of the wild-type CaR and a positive modulator of E837A mutant CaR, and the positive modulation critically depends on the primary amine in JKJ05 which appears to interact with residue E767 in this model. Phenylalkylamines structurally related to NPS R-568 are proposed to bind to pocket P2, and they anchor to the pocket through a critical salt bridge between their positively charged central amino group and the acidic residue E837 in TM7.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401263&req=5

fig03: Schematic representation of the CaR 7TM. Molecular docking results indicated two potential binding pockets for allosteric modulators within the upper part of the transmembrane helical bundle. The red circle indicates pocket P1, enclosed within TM3 (green), TM4 (purple), TM5 (blue), TM6 (brown) and exo-loop2; the blue circle indicates pocket P2, enclosed within TM1 (cyan), TM2 (orange), TM3, TM6, TM7 (yellow-green) and exo-loop 2. Residues E767, E837, and the conserved disulphide bond (C677–C765) connecting exo-loop 1 and 2 are shown as Corey-Pauling-Koltun. Compound 1 and its analogue JKJ05 are proposed to bind to pocket P1. JKJ05 is a negative modulator of the wild-type CaR and a positive modulator of E837A mutant CaR, and the positive modulation critically depends on the primary amine in JKJ05 which appears to interact with residue E767 in this model. Phenylalkylamines structurally related to NPS R-568 are proposed to bind to pocket P2, and they anchor to the pocket through a critical salt bridge between their positively charged central amino group and the acidic residue E837 in TM7.
Mentions: Negative modulators of the CaR, so-called calcilytic drugs such as NPS2143 [75], NPS89636 [76], Calhex-231 [42], Compound 1 [77] and certain derivatives of NPS2143 [78, 79] block Ca2+ activation of the CaR. These compounds, except Compound 1, are phenylalkylamines structurally related to those type II calcimimetics demonstrating that subtle differences in the configuration of compounds binding to the CaR 7TM might either prevent (negative modulators) or promote (positive modulators) helical motion required for receptor activation. Negative modulation of the CaR by NPS2143 and Calhex-231 also critically depend on residue E837 located in the TM7 (Fig. 3) [42, 43]. Both compounds are primarily anchored through an H-bond assisted salt bridge to this negatively charged residue.

Bottom Line: The human extracellular Ca(2+)-sensing receptor (CaR), a member of the G protein-coupled receptor family 3, plays a key role in the regulation of extracellular calcium homeostasis.It is one of just a few G protein-coupled receptors with a large number of naturally occurring mutations identified in patients.In contrast to the small sizes of its agonists, this large dimeric receptor consists of domains with topologically distinctive orthosteric and allosteric sites.

View Article: PubMed Central - PubMed

Affiliation: Molecular Signalling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. jianxinh@niddk.nih.gov

ABSTRACT
The human extracellular Ca(2+)-sensing receptor (CaR), a member of the G protein-coupled receptor family 3, plays a key role in the regulation of extracellular calcium homeostasis. It is one of just a few G protein-coupled receptors with a large number of naturally occurring mutations identified in patients. In contrast to the small sizes of its agonists, this large dimeric receptor consists of domains with topologically distinctive orthosteric and allosteric sites. Information derived from studies of naturally occurring mutations, engineered mutations, allosteric modulators and crystal structures of the agonist-binding domain of homologous type 1 metabotropic glutamate receptor and G protein-coupled rhodopsin offers new insights into the structure and function of the CaR.

Show MeSH