Towards a Structural Understanding of Allosteric Drugs at the Human Calcium-sensing Receptor

Overview

Journal Cell Res

Specialty Cell Biology

Date 2016 Mar 23

PMID 27002221

Citations 52

Authors

Katie Leach

Karen J Gregory

Irina Kufareva

Elham Khajehali

Anna E Cook

Ruben Abagyan

Arthur D Conigrave

Patrick M Sexton

Arthur Christopoulos

Affiliations

Soon will be listed here.

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.

Citing Articles

Comparative Study of Allosteric GPCR Binding Sites and Their Ligandability Potential.

Peter S, Siragusa L, Thomas M, Palomba T, Cross S, OBoyle N J Chem Inf Model. 2024; 64(21):8176-8192.

PMID: 39441864 PMC: 11558664. DOI: 10.1021/acs.jcim.4c00819.

New calcimimetics for secondary hyperparathyroidism in CKD G5D: do they offer advantages?.

Negri A, Bover J, Vervloet M, Cozzolino M J Nephrol. 2024; .

PMID: 39404956 DOI: 10.1007/s40620-024-02119-y.

Measuring Calcium-Sensing Receptor Agonist-Driven Insertional Signaling (ADIS) and Trafficking by TIRF Microscopy.

Gorvin C Methods Mol Biol. 2024; 2861:111-126.

PMID: 39395101 DOI: 10.1007/978-1-0716-4164-4_9.

Measuring IP3 Generation in Real-Time Using a NanoBiT Luminescence Biosensor.

Gorvin C Methods Mol Biol. 2024; 2861:33-42.

PMID: 39395095 DOI: 10.1007/978-1-0716-4164-4_3.

Large library docking identifies positive allosteric modulators of the calcium-sensing receptor.

Liu F, Wu C, Tu C, Glenn I, Meyerowitz J, Kaplan A Science. 2024; 385(6715):eado1868.

PMID: 39298584 PMC: 11629082. DOI: 10.1126/science.ado1868.

References

Gowen M, Stroup G, Dodds R, James I, Votta B, Smith B . Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats. J Clin Invest. 2000; 105(11):1595-604. PMC: 300853. DOI: 10.1172/JCI9038. View

Abagyan R, Totrov M . Biased probability Monte Carlo conformational searches and electrostatic calculations for peptides and proteins. J Mol Biol. 1994; 235(3):983-1002. DOI: 10.1006/jmbi.1994.1052. View

Hauache O, Hu J, Ray K, Xie R, Jacobson K, Spiegel A . Effects of a calcimimetic compound and naturally activating mutations on the human Ca2+ receptor and on Ca2+ receptor/metabotropic glutamate chimeric receptors. Endocrinology. 2000; 141(11):4156-63. PMC: 11682860. DOI: 10.1210/endo.141.11.7753. View

Freichel M, Holloschi A, Hafner M, Flockerzi V, Raue F . Expression of a calcium-sensing receptor in a human medullary thyroid carcinoma cell line and its contribution to calcitonin secretion. Endocrinology. 1996; 137(9):3842-8. DOI: 10.1210/endo.137.9.8756555. View

Christopoulos A . Assessing the distribution of parameters in models of ligand-receptor interaction: to log or not to log. Trends Pharmacol Sci. 1998; 19(9):351-7. DOI: 10.1016/s0165-6147(98)01240-1. View

Mun H, Franks A, Culverston E, Krapcho K, Nemeth E, Conigrave A . The Venus Fly Trap domain of the extracellular Ca2+ -sensing receptor is required for L-amino acid sensing. J Biol Chem. 2004; 279(50):51739-44. DOI: 10.1074/jbc.M406164/200. View

Ray K, Tisdale J, Dodd R, Dauban P, Ruat M, Northup J . Calindol, a positive allosteric modulator of the human Ca(2+) receptor, activates an extracellular ligand-binding domain-deleted rhodopsin-like seven-transmembrane structure in the absence of Ca(2+). J Biol Chem. 2005; 280(44):37013-20. DOI: 10.1074/jbc.M506681200. View

Hu J, Jiang J, Costanzi S, Thomas C, Yang W, Feyen J . A missense mutation in the seven-transmembrane domain of the human Ca2+ receptor converts a negative allosteric modulator into a positive allosteric modulator. J Biol Chem. 2006; 281(30):21558-21565. DOI: 10.1074/jbc.M603682200. View

Muto T, Tsuchiya D, Morikawa K, Jingami H . Structures of the extracellular regions of the group II/III metabotropic glutamate receptors. Proc Natl Acad Sci U S A. 2007; 104(10):3759-64. PMC: 1820657. DOI: 10.1073/pnas.0611577104. View

10.

Leach K, Sexton P, Christopoulos A . Allosteric GPCR modulators: taking advantage of permissive receptor pharmacology. Trends Pharmacol Sci. 2007; 28(8):382-9. DOI: 10.1016/j.tips.2007.06.004. View

11.

Chen Y, Goudet C, Pin J, Conn P . N-{4-Chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA) acts through a novel site as a positive allosteric modulator of group 1 metabotropic glutamate receptors. Mol Pharmacol. 2007; 73(3):909-18. DOI: 10.1124/mol.107.040097. View

12.

Bu L, Michino M, Wolf R, Brooks 3rd C . Improved model building and assessment of the Calcium-sensing receptor transmembrane domain. Proteins. 2007; 71(1):215-26. DOI: 10.1002/prot.21685. View

13.

Christopoulos A . Advances in G protein-coupled receptor allostery: from function to structure. Mol Pharmacol. 2014; 86(5):463-78. DOI: 10.1124/mol.114.094342. View

14.

Cook A, Mistry S, Gregory K, Furness S, Sexton P, Scammells P . Biased allosteric modulation at the CaS receptor engendered by structurally diverse calcimimetics. Br J Pharmacol. 2014; 172(1):185-200. PMC: 4280977. DOI: 10.1111/bph.12937. View

15.

Rovira X, Malhaire F, Scholler P, Rodrigo J, Gonzalez-Bulnes P, Llebaria A . Overlapping binding sites drive allosteric agonism and positive cooperativity in type 4 metabotropic glutamate receptors. FASEB J. 2014; 29(1):116-30. DOI: 10.1096/fj.14-257287. View

16.

Monn J, Prieto L, Taboada L, Pedregal C, Hao J, Reinhard M . Synthesis and pharmacological characterization of C4-disubstituted analogs of 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate: identification of a potent, selective metabotropic glutamate receptor agonist and determination of agonist-bound.... J Med Chem. 2015; 58(4):1776-94. DOI: 10.1021/jm501612y. View

17.

Leach K, Conigrave A, Sexton P, Christopoulos A . Towards tissue-specific pharmacology: insights from the calcium-sensing receptor as a paradigm for GPCR (patho)physiological bias. Trends Pharmacol Sci. 2015; 36(4):215-25. DOI: 10.1016/j.tips.2015.02.004. View

18.

Yarova P, Stewart A, Sathish V, Britt Jr R, Thompson M, Lowe A . Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma. Sci Transl Med. 2015; 7(284):284ra60. PMC: 4725057. DOI: 10.1126/scitranslmed.aaa0282. View

19.

Stiefl N, Gedeck P, Chin D, Hunt P, Lindvall M, Spiegel K . FOCUS--Development of a Global Communication and Modeling Platform for Applied and Computational Medicinal Chemists. J Chem Inf Model. 2015; 55(4):896-908. DOI: 10.1021/ci500598e. View

20.

Christopher J, Aves S, Bennett K, Dore A, Errey J, Jazayeri A . Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu5 Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile). J Med Chem. 2015; 58(16):6653-64. DOI: 10.1021/acs.jmedchem.5b00892. View