Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs

Ron Dror, Hillary F Green, Celine Valant, David W Borhani, James R Valcourt, Albert C Pan, Daniel H Arlow, Meritxell Canals, Jonathan Robert David Lane, Raphael Steve Rahmani, Jonathan Bayldon Baell, Patrick Sexton, Arthur Christopoulos, David E Shaw

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The design of G-protein-coupled receptor (GPCR) allosteric modulators, an active area of modern pharmaceutical research, has proved challenging because neither the binding modes nor the molecular mechanisms of such drugs are known. Here we determine binding sites, bound conformations and specific drug-receptor interactions for several allosteric modulators of the M2 muscarinic acetylcholine receptor (M2 receptor), a prototypical family A GPCR, using atomic-level simulations in which the modulators spontaneously associate with the receptor. Despite substantial structural diversity, all modulators form cation-p interactions with clusters of aromatic residues in the receptor extracellular vestibule, approximately 15 ? from the classical, orthosteric ligand-binding site. We validate the observed modulator binding modes through radioligand binding experiments on receptor mutants designed, on the basis of our simulations, either to increase or to decrease modulator affinity. Simulations also revealed mechanisms that contribute to positive and negative allosteric modulation of classical ligand binding, including coupled conformational changes of the two binding sites and electrostatic interactions between ligands in these sites. These observations enabled the design of chemical modifications that substantially alter a modulator s allosteric effects. Our findings thus provide a structural basis for the rational design of allosteric modulators targeting muscarinic and possibly other GPCRs.
Original languageEnglish
Pages (from-to)295 - 299
Number of pages5
JournalNature
Volume503
Issue number7475
DOIs
Publication statusPublished - 2013

Cite this

Dror, R., Green, H. F., Valant, C., Borhani, D. W., Valcourt, J. R., Pan, A. C., ... Shaw, D. E. (2013). Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs. Nature, 503(7475), 295 - 299. https://doi.org/10.1038/nature12595
Dror, Ron ; Green, Hillary F ; Valant, Celine ; Borhani, David W ; Valcourt, James R ; Pan, Albert C ; Arlow, Daniel H ; Canals, Meritxell ; Lane, Jonathan Robert David ; Rahmani, Raphael Steve ; Baell, Jonathan Bayldon ; Sexton, Patrick ; Christopoulos, Arthur ; Shaw, David E. / Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs. In: Nature. 2013 ; Vol. 503, No. 7475. pp. 295 - 299.
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abstract = "The design of G-protein-coupled receptor (GPCR) allosteric modulators, an active area of modern pharmaceutical research, has proved challenging because neither the binding modes nor the molecular mechanisms of such drugs are known. Here we determine binding sites, bound conformations and specific drug-receptor interactions for several allosteric modulators of the M2 muscarinic acetylcholine receptor (M2 receptor), a prototypical family A GPCR, using atomic-level simulations in which the modulators spontaneously associate with the receptor. Despite substantial structural diversity, all modulators form cation-p interactions with clusters of aromatic residues in the receptor extracellular vestibule, approximately 15 ? from the classical, orthosteric ligand-binding site. We validate the observed modulator binding modes through radioligand binding experiments on receptor mutants designed, on the basis of our simulations, either to increase or to decrease modulator affinity. Simulations also revealed mechanisms that contribute to positive and negative allosteric modulation of classical ligand binding, including coupled conformational changes of the two binding sites and electrostatic interactions between ligands in these sites. These observations enabled the design of chemical modifications that substantially alter a modulator s allosteric effects. Our findings thus provide a structural basis for the rational design of allosteric modulators targeting muscarinic and possibly other GPCRs.",
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Dror, R, Green, HF, Valant, C, Borhani, DW, Valcourt, JR, Pan, AC, Arlow, DH, Canals, M, Lane, JRD, Rahmani, RS, Baell, JB, Sexton, P, Christopoulos, A & Shaw, DE 2013, 'Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs' Nature, vol. 503, no. 7475, pp. 295 - 299. https://doi.org/10.1038/nature12595

Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs. / Dror, Ron; Green, Hillary F; Valant, Celine; Borhani, David W; Valcourt, James R; Pan, Albert C; Arlow, Daniel H; Canals, Meritxell; Lane, Jonathan Robert David; Rahmani, Raphael Steve; Baell, Jonathan Bayldon; Sexton, Patrick; Christopoulos, Arthur; Shaw, David E.

In: Nature, Vol. 503, No. 7475, 2013, p. 295 - 299.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Dror, Ron

AU - Green, Hillary F

AU - Valant, Celine

AU - Borhani, David W

AU - Valcourt, James R

AU - Pan, Albert C

AU - Arlow, Daniel H

AU - Canals, Meritxell

AU - Lane, Jonathan Robert David

AU - Rahmani, Raphael Steve

AU - Baell, Jonathan Bayldon

AU - Sexton, Patrick

AU - Christopoulos, Arthur

AU - Shaw, David E

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N2 - The design of G-protein-coupled receptor (GPCR) allosteric modulators, an active area of modern pharmaceutical research, has proved challenging because neither the binding modes nor the molecular mechanisms of such drugs are known. Here we determine binding sites, bound conformations and specific drug-receptor interactions for several allosteric modulators of the M2 muscarinic acetylcholine receptor (M2 receptor), a prototypical family A GPCR, using atomic-level simulations in which the modulators spontaneously associate with the receptor. Despite substantial structural diversity, all modulators form cation-p interactions with clusters of aromatic residues in the receptor extracellular vestibule, approximately 15 ? from the classical, orthosteric ligand-binding site. We validate the observed modulator binding modes through radioligand binding experiments on receptor mutants designed, on the basis of our simulations, either to increase or to decrease modulator affinity. Simulations also revealed mechanisms that contribute to positive and negative allosteric modulation of classical ligand binding, including coupled conformational changes of the two binding sites and electrostatic interactions between ligands in these sites. These observations enabled the design of chemical modifications that substantially alter a modulator s allosteric effects. Our findings thus provide a structural basis for the rational design of allosteric modulators targeting muscarinic and possibly other GPCRs.

AB - The design of G-protein-coupled receptor (GPCR) allosteric modulators, an active area of modern pharmaceutical research, has proved challenging because neither the binding modes nor the molecular mechanisms of such drugs are known. Here we determine binding sites, bound conformations and specific drug-receptor interactions for several allosteric modulators of the M2 muscarinic acetylcholine receptor (M2 receptor), a prototypical family A GPCR, using atomic-level simulations in which the modulators spontaneously associate with the receptor. Despite substantial structural diversity, all modulators form cation-p interactions with clusters of aromatic residues in the receptor extracellular vestibule, approximately 15 ? from the classical, orthosteric ligand-binding site. We validate the observed modulator binding modes through radioligand binding experiments on receptor mutants designed, on the basis of our simulations, either to increase or to decrease modulator affinity. Simulations also revealed mechanisms that contribute to positive and negative allosteric modulation of classical ligand binding, including coupled conformational changes of the two binding sites and electrostatic interactions between ligands in these sites. These observations enabled the design of chemical modifications that substantially alter a modulator s allosteric effects. Our findings thus provide a structural basis for the rational design of allosteric modulators targeting muscarinic and possibly other GPCRs.

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