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Review ArticleReview Article

The Significance of G Protein-Coupled Receptor Crystallography for Drug Discovery

John A. Salon, David T. Lodowski and Krzysztof Palczewski
Dianne M. Perez, ASSOCIATE EDITOR
Pharmacological Reviews December 2011, 63 (4) 901-937; DOI: https://doi.org/10.1124/pr.110.003350
John A. Salon
Department of Molecular Structure, Amgen Incorporated, Thousand Oaks, California (J.A.S.); and Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio (D.T.L., K.P.)
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David T. Lodowski
Department of Molecular Structure, Amgen Incorporated, Thousand Oaks, California (J.A.S.); and Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio (D.T.L., K.P.)
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Krzysztof Palczewski
Department of Molecular Structure, Amgen Incorporated, Thousand Oaks, California (J.A.S.); and Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio (D.T.L., K.P.)
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Dianne M. Perez
Department of Molecular Structure, Amgen Incorporated, Thousand Oaks, California (J.A.S.); and Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio (D.T.L., K.P.)
Roles: ASSOCIATE EDITOR
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Abstract

Crucial as molecular sensors for many vital physiological processes, seven-transmembrane domain G protein-coupled receptors (GPCRs) comprise the largest family of proteins targeted by drug discovery. Together with structures of the prototypical GPCR rhodopsin, solved structures of other liganded GPCRs promise to provide insights into the structural basis of the superfamily's biochemical functions and assist in the development of new therapeutic modalities and drugs. One of the greatest technical and theoretical challenges to elucidating and exploiting structure-function relationships in these systems is the emerging concept of GPCR conformational flexibility and its cause-effect relationship for receptor-receptor and receptor-effector interactions. Such conformational changes can be subtle and triggered by relatively small binding energy effects, leading to full or partial efficacy in the activation or inactivation of the receptor system at large. Pharmacological dogma generally dictates that these changes manifest themselves through kinetic modulation of the receptor's G protein partners. Atomic resolution information derived from increasingly available receptor structures provides an entrée to the understanding of these events and practically applying it to drug design. Supported by structure-activity relationship information arising from empirical screening, a unified structural model of GPCR activation/inactivation promises to both accelerate drug discovery in this field and improve our fundamental understanding of structure-based drug design in general. This review discusses fundamental problems that persist in drug design and GPCR structural determination.

Footnotes

  • All authors contributed equally to this work.

  • This article is available online at http://pharmrev.aspetjournals.org.

    doi:10.1124/pr.110.003350.

  • © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 63 (4)
Pharmacological Reviews
Vol. 63, Issue 4
1 Dec 2011
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Review ArticleReview Article

GPCRs AND DRUG DISCOVERY

John A. Salon, David T. Lodowski and Krzysztof Palczewski
Pharmacological Reviews December 1, 2011, 63 (4) 901-937; DOI: https://doi.org/10.1124/pr.110.003350

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Review ArticleReview Article

GPCRs AND DRUG DISCOVERY

John A. Salon, David T. Lodowski and Krzysztof Palczewski
Pharmacological Reviews December 1, 2011, 63 (4) 901-937; DOI: https://doi.org/10.1124/pr.110.003350
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  • Article
    • Abstract
    • I. Introduction
    • II. Current Challenges and Opportunities in G Protein-Coupled Receptor Drug Discovery
    • III. History of G Protein-Coupled Receptor Structural Clarification
    • IV. Advances in G Protein-Coupled Receptor Structural Determination
    • V. Ramifications for G Protein-Coupled Receptor Drug Discovery
    • VI. Unresolved Issues and Concluding Remarks
    • Acknowledgments
    • Authorship Contributions
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