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Towards a structural understanding of allosteric drugs at the human calcium-sensing receptor.

ABSTRACT: Drugs that allosterically target the human calcium-sensing receptor (CaSR) have substantial therapeutic potential, but are currently limited. Given the absence of high-resolution structures of the CaSR, we combined mutagenesis with a novel analytical approach and molecular modeling to develop an "enriched" picture of structure-function requirements for interaction between Ca(2+)o and allosteric modulators within the CaSR's 7 transmembrane (7TM) domain. An extended cavity that accommodates multiple binding sites for structurally diverse ligands was identified. Phenylalkylamines bind to a site that overlaps with a putative Ca(2+)o-binding site and extends towards an extracellular vestibule. In contrast, the structurally and pharmacologically distinct AC-265347 binds deeper within the 7TM domains. Furthermore, distinct amino acid networks were found to mediate cooperativity by different modulators. These findings may facilitate the rational design of allosteric modulators with distinct and potentially pathway-biased pharmacological effects.

SUBMITTER: Leach K

PROVIDER: S-EPMC4856764 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Towards a structural understanding of allosteric drugs at the human calcium-sensing receptor.

Leach Katie K Gregory Karen J KJ Kufareva Irina I Khajehali Elham E Cook Anna E AE Abagyan Ruben R Conigrave Arthur D AD Sexton Patrick M PM Christopoulos Arthur A

Cell research 20160322 5

Drugs that allosterically target the human calcium-sensing receptor (CaSR) have substantial therapeutic potential, but are currently limited. Given the absence of high-resolution structures of the CaSR, we combined mutagenesis with a novel analytical approach and molecular modeling to develop an "enriched" picture of structure-function requirements for interaction between Ca(2+)o and allosteric modulators within the CaSR's 7 transmembrane (7TM) domain. An extended cavity that accommodates multip ...[more]

PMID: 27002221

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Project description:Background and purposeStrontium ranelate, a drug approved and until recently used for the treatment of osteoporosis, mediates its effects on bone at least in part via the calcium-sensing (CaS) receptor. However, it is not known whether bone-targeted CaS receptor positive allosteric modulators (PAMs; calcimimetics) represent an alternative (or adjunctive) therapy to strontium (Sr2+ o ).Experimental approachWe assessed three structurally distinct calcimimetics [cinacalcet, AC-265347 and a benzothiazole tri-substituted urea (BTU-compound 13)], alone and in combination with extracellular calcium (Ca2+ o ) or Sr2+ o , in G protein-dependent signalling assays and trafficking experiments in HEK293 cells and their effects on cell differentiation, tartrate-resistant acid phosphatase (TRAP) activity and hydroxyapatite resorption assays in human blood-derived osteoclasts.Key resultsSr2+ o activated CaS receptor-dependent signalling in HEK293 cells in a similar manner to Ca2+ o , and inhibited the maturation, TRAP expression and hydroxyapatite resorption capacity of human osteoclasts. Calcimimetics potentiated Ca2+ o - and Sr2+ o -mediated CaS receptor signalling in HEK293 cells with distinct biased profiles, and only cinacalcet chaperoned an endoplasmic reticulum-retained CaS mutant receptor to the cell surface in HEK293 cells, indicative of a conformational state different from that engendered by AC-265347 and BTU-compound 13. Intriguingly, only cinacalcet modulated human osteoclast function, reducing TRAP activity and profoundly inhibiting resorption.Conclusion and implicationsAlthough AC-265347 and BTU-compound 13 potentiated Ca2+ o - and Sr2+ o -induced CaS receptor activation, they neither replicated nor potentiated the ability of Sr2+ o to inhibit human osteoclast function. In contrast, the FDA-approved calcimimetic, cinacalcet, inhibited osteoclast TRAP activity and hydroxyapatite resorption, which may contribute to its clinical effects on bone mineral density LINKED ARTICLES: This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc.

Dataset Information

Towards a structural understanding of allosteric drugs at the human calcium-sensing receptor.

Publications

Towards a structural understanding of allosteric drugs at the human calcium-sensing receptor.

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