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Review ArticleMINIREVIEW

Structural Mimicry in G Protein-Coupled Receptors: Implications of the High-Resolution Structure of Rhodopsin for Structure-Function Analysis of Rhodopsin-Like Receptors

Juan A. Ballesteros, Lei Shi and Jonathan A. Javitch
Molecular Pharmacology July 2001, 60 (1) 1-19; DOI: https://doi.org/10.1124/mol.60.1.1
Juan A. Ballesteros
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Lei Shi
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Jonathan A. Javitch
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This article has a correction. Please see:

  • Correction to “Structural mimicry in G protein-coupled receptors: implications of the high-resolution structure of rhodopsin for structure-function analysis of rhodopsin-like receptors” - January 01, 2002

Abstract

The availability of a high-resolution structure of rhodopsin now allows us to reconsider research attempts to understand structure-function relationships in other G protein-coupled receptors (GPCRs). A comparison of the rhodopsin structure with the results of previous sequence analysis and molecular modeling that incorporated experimental results demonstrates a high degree of success for these methods in predicting the helix ends and protein-protein interface of GPCRs. Moreover, the amino acid residues inferred to form the surface of the binding-site crevice based on our application of the substituted-cysteine accessibility method in the dopamine D2 receptor are in remarkable agreement with the rhodopsin structure, with the notable exception of some residues in the fourth transmembrane segment. Based on our analysis of the data reviewed, we propose that the overall structures of rhodopsin and of amine receptors are very similar, although we also identified localized regions where the structure of these receptors may diverge. We further propose that several of the highly unusual structural features of rhodopsin are also present in amine GPCRs, despite the absence of amino acids that might have thought to have been critical to the adoption of these features. Thus, different amino acids or alternate microdomains can support similar deviations from regular α-helical structure, thereby resulting in similar tertiary structure. Such structural mimicry is a mechanism by which a common ancestor could diverge sufficiently to develop the selectivity necessary to interact with diverse signals, while still maintaining a similar overall fold. Through this process, the core function of signaling activation through a conformational change in the transmembrane segments that alters the conformation of the cytoplasmic surface and subsequent interaction with G proteins is presumably shared by the entire Class A family of receptors, despite their selectivity for a diverse group of ligands.

  • Abbreviations

    GPCRs
    G protein coupled receptors
    TM
    transmembrane segment
    SASA
    solvent accessible surface area
    SCAM
    substituted-cysteine accessibility method
    MTS
    methanethiosulfonate
    RMSD
    root mean square distance
    IpBABC
    p-(bromoacetamido)benzyl-1-[125I]iodocarazolol
    E2
    second extracellular loop
    MD
    molecular dynamics. Receptor abbreviations: 5H1A (5H1B, 5H2A), 5-hydroxytryptamine 1A (1B, 2A) receptor
    A1AA (A1AB
    A2AA), α1A (1B, 2A) adrenergic receptor
    AA1R (AA2A)
    adenosine A1 (A2A) receptor
    ACM1 (ACM2
    ACM3, ACM5), muscarinic acetylcholine M1 (M2, M3, M5) receptor
    ACTR
    adrenocorticotropin receptor
    AG2R
    type-1 angiotensin II receptor
    B2AR
    β2 adrenergic receptor
    D2DR
    dopamine D2 receptor
    ETBR
    endothelin B receptor
    ET1R
    endothelin-1 receptor
    GASR
    gastrin/cholecystokinin type B receptor
    GRHR
    gonadotropin-releasing hormone receptor
    HH2R
    histamine H2 receptor
    MSHR
    melanocyte stimulating hormone receptor
    NK1R
    substance-P receptor
    NK2R
    substance-K receptor
    NTR1
    neurotensin type I receptor
    OPRK
    κ-type opioid receptor
    OPSD
    rhodopsin
    P2UR
    P2U purinoceptor 1
    P2YR
    P2Y purinoceptor 1
    PAFR
    platelet activating factor receptor
    TSHR
    thyrotropin receptor
    • Received February 12, 2001.
    • Accepted April 10, 2001.
    • The American Society for Pharmacology and Experimental Therapeutics
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    Molecular Pharmacology: 60 (1)
    Molecular Pharmacology
    Vol. 60, Issue 1
    1 Jul 2001
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    Review ArticleMINIREVIEW

    Structural Mimicry in G Protein-Coupled Receptors: Implications of the High-Resolution Structure of Rhodopsin for Structure-Function Analysis of Rhodopsin-Like Receptors

    Juan A. Ballesteros, Lei Shi and Jonathan A. Javitch
    Molecular Pharmacology July 1, 2001, 60 (1) 1-19; DOI: https://doi.org/10.1124/mol.60.1.1

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    Review ArticleMINIREVIEW

    Structural Mimicry in G Protein-Coupled Receptors: Implications of the High-Resolution Structure of Rhodopsin for Structure-Function Analysis of Rhodopsin-Like Receptors

    Juan A. Ballesteros, Lei Shi and Jonathan A. Javitch
    Molecular Pharmacology July 1, 2001, 60 (1) 1-19; DOI: https://doi.org/10.1124/mol.60.1.1
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