Novel Allosteric Modulators of G Protein-coupled Receptors

Patrick R Gentry; Patrick M Sexton; Arthur Christopoulos

doi:10.1074/jbc.r115.662759

Novel Allosteric Modulators of G Protein-coupled Receptors

Patrick R Gentry, Patrick M Sexton, Arthur Christopoulos

108 Citations (Scopus)

Abstract

G protein-coupled receptors (GPCRs) are allosteric proteins, because their signal transduction relies on interactions between topographically distinct, yet conformationally linked, domains. Much of the focus on GPCR allostery in the new millennium, however, has been on modes of targeting GPCR allosteric sites with chemical probes due to the potential for novel therapeutics. It is now apparent that some GPCRs possess more than one targetable allosteric site, in addition to a growing list of putative endogenous modulators. Advances in structural biology are also shedding new insights into mechanisms of allostery, although the complexities of candidate allosteric drugs necessitate rigorous biological characterization.

Original language	English
Journal	The Journal of Biological Chemistry
Volume	290
Issue number	32
Pages (from-to)	19478-88
Number of pages	11
ISSN	0021-9258
DOIs	https://doi.org/10.1074/jbc.r115.662759
Publication status	Published - 7 Aug 2015
Externally published	Yes

Keywords

Allosteric Regulation
Allosteric Site/drug effects
Crystallography, X-Ray/history
Drug Design
History, 21st Century
Humans
Ligands
Models, Molecular
Protein Binding
Protein Structure, Tertiary
Receptors, G-Protein-Coupled/agonists
Signal Transduction
Small Molecule Libraries/chemical synthesis
Structure-Activity Relationship

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http://europepmc.org/articles/pmc4528113?pdf=render

Cite this

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title = "Novel Allosteric Modulators of G Protein-coupled Receptors",

abstract = "G protein-coupled receptors (GPCRs) are allosteric proteins, because their signal transduction relies on interactions between topographically distinct, yet conformationally linked, domains. Much of the focus on GPCR allostery in the new millennium, however, has been on modes of targeting GPCR allosteric sites with chemical probes due to the potential for novel therapeutics. It is now apparent that some GPCRs possess more than one targetable allosteric site, in addition to a growing list of putative endogenous modulators. Advances in structural biology are also shedding new insights into mechanisms of allostery, although the complexities of candidate allosteric drugs necessitate rigorous biological characterization. ",

keywords = "Allosteric Regulation, Allosteric Site/drug effects, Crystallography, X-Ray/history, Drug Design, History, 21st Century, Humans, Ligands, Models, Molecular, Protein Binding, Protein Structure, Tertiary, Receptors, G-Protein-Coupled/agonists, Signal Transduction, Small Molecule Libraries/chemical synthesis, Structure-Activity Relationship",

author = "Gentry, {Patrick R} and Sexton, {Patrick M} and Arthur Christopoulos",

note = "{\textcopyright} 2015 by The American Society for Biochemistry and Molecular Biology, Inc.",

year = "2015",

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doi = "10.1074/jbc.r115.662759",

language = "English",

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journal = "Journal of Biological Chemistry",

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T1 - Novel Allosteric Modulators of G Protein-coupled Receptors

AU - Gentry, Patrick R

AU - Sexton, Patrick M

AU - Christopoulos, Arthur

PY - 2015/8/7

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N2 - G protein-coupled receptors (GPCRs) are allosteric proteins, because their signal transduction relies on interactions between topographically distinct, yet conformationally linked, domains. Much of the focus on GPCR allostery in the new millennium, however, has been on modes of targeting GPCR allosteric sites with chemical probes due to the potential for novel therapeutics. It is now apparent that some GPCRs possess more than one targetable allosteric site, in addition to a growing list of putative endogenous modulators. Advances in structural biology are also shedding new insights into mechanisms of allostery, although the complexities of candidate allosteric drugs necessitate rigorous biological characterization.

AB - G protein-coupled receptors (GPCRs) are allosteric proteins, because their signal transduction relies on interactions between topographically distinct, yet conformationally linked, domains. Much of the focus on GPCR allostery in the new millennium, however, has been on modes of targeting GPCR allosteric sites with chemical probes due to the potential for novel therapeutics. It is now apparent that some GPCRs possess more than one targetable allosteric site, in addition to a growing list of putative endogenous modulators. Advances in structural biology are also shedding new insights into mechanisms of allostery, although the complexities of candidate allosteric drugs necessitate rigorous biological characterization.

KW - Allosteric Regulation

KW - Allosteric Site/drug effects

KW - Crystallography, X-Ray/history

KW - Drug Design

KW - History, 21st Century

KW - Humans

KW - Ligands

KW - Models, Molecular

KW - Protein Binding

KW - Protein Structure, Tertiary

KW - Receptors, G-Protein-Coupled/agonists

KW - Signal Transduction

KW - Small Molecule Libraries/chemical synthesis

KW - Structure-Activity Relationship

U2 - 10.1074/jbc.r115.662759

DO - 10.1074/jbc.r115.662759

M3 - Review

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SN - 0021-9258

VL - 290

SP - 19478

EP - 19488

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 32

ER -

Novel Allosteric Modulators of G Protein-coupled Receptors

Abstract

Keywords

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