Elsevier

Life Sciences

Volume 86, Issues 15–16, 10 April 2010, Pages 590-597
Life Sciences

Minireview
Increasingly accurate dynamic molecular models of G-protein coupled receptor oligomers: Panacea or Pandora's box for novel drug discovery?

https://doi.org/10.1016/j.lfs.2009.05.004Get rights and content

Abstract

For years, conventional drug design at G-protein coupled receptors (GPCRs) has mainly focused on the inhibition of a single receptor at a usually well-defined ligand-binding site. The recent discovery of more and more physiologically relevant GPCR dimers/oligomers suggests that selectively targeting these complexes or designing small molecules that inhibit receptor–receptor interactions might provide new opportunities for novel drug discovery. To uncover the fundamental mechanisms and dynamics governing GPCR dimerization/oligomerization, it is crucial to understand the dynamic process of receptor–receptor association, and to identify regions that are suitable for selective drug binding. This minireview highlights current progress in the development of increasingly accurate dynamic molecular models of GPCR oligomers based on structural, biochemical, and biophysical information that has recently appeared in the literature. In view of this new information, there has never been a more exciting time for computational research into GPCRs than at present. Information-driven modern molecular models of GPCR complexes are expected to efficiently guide the rational design of GPCR oligomer-specific drugs, possibly allowing researchers to reach for the high-hanging fruits in GPCR drug discovery, i.e. more potent and selective drugs for efficient therapeutic interventions.

Introduction

G-protein coupled receptors (GPCRs) are abundant membrane proteins consisting of an extracellular N-terminus, seven highly conserved transmembrane (TM) domains, three intracellular (IC) and three extracellular (EC) loops, and an intracellular C-terminus. Despite their architectural homology, GPCRs can respond to diverse stimuli and initiate various intracellular signaling cascades (Luttrell 2008) in either G-protein-dependent or independent manners (Delcourt et al., 2007, Lefkowitz, 2007). As a result, GPCRs mediate a variety of physiological and pathophysiological processes (Thompson et al. 2008), are the primary targets for about 30% of prescription drugs (Overington et al. 2006), and are likely to be potential targets for new therapeutic drugs (Xiao et al. 2008).

Targeting the orthosteric ligand-binding sites (i.e. the same binding sites recognized by endogenous ligands) of GPCRs for the development of therapeutic drugs has engaged, and continues to engage, many academic researchers and pharmaceutical industries (Lagerstrom and Schioth 2008). However, the growing body of evidence that GPCRs form clinically relevant dimers/oligomers with implications in pain (Finley et al., 2008, Waldhoer et al., 2005), asthma (McGraw et al. 2006), Parkinson's disease (Carriba et al. 2007), schizophrenia (Gonzalez-Maeso et al. 2008), pre-eclampsia hypertension (AbdAlla et al. 2001), and hypogonadotropic hypogonadism (Leanos-Miranda et al. 2005), has generated a great interest in GPCR dimers/oligomers as exciting new targets for novel drug discovery (Panetta and Greenwood 2008).

Small-molecule drug discovery at GPCR dimers is certainly more challenging than conventional GPCR drug discovery at single orthosteric ligand-binding sites, but represents an innovative direction for the 21st century medicine. One of the fundamental challenges in developing GPCR dimer-specific drugs is to understand the mechanisms and dynamics governing the interaction between receptor pairs and/or higher-order oligomers. Despite the numerous efforts to explore this issue, the information available is still very limited. This minireview summarizes current progress in the development of increasingly accurate computational models of GPCR oligomers using important structural, biochemical, and biophysical information that has become available in recent literature. These computational models further refined on the basis of detailed structural and dynamic information derived from experiments may provide a more complete understanding of the molecular and energetic basis of GPCR oligomerization, thus facilitating the design of novel GPCR oligomer-specific drugs.

Section snippets

New structural templates for GPCR monomeric models

Over the last ten years, the number of GPCR crystal structures has increased remarkably going from the single crystal structure of bovine rhodopsin in year 2000 (Palczewski et al. 2000) to twenty-four different crystal structures of rhodopsin-like class A GPCRs in year 2008 (Bortolato et al. 2009). Specifically, high-resolution crystal structures are currently available for native and mutant bovine rhodopsin (Li et al., 2004, Nakamichi et al., 2007, Nakamichi and Okada, 2006a, Nakamichi and

New biochemical and biophysical data for GPCR oligomeric models

More and more experimental data support the view that GPCRs exist and function as contact dimers or higher-order oligomers with TM regions at the interfaces. In contact dimers/oligomers of GPCRs, the original TM helical-bundle topology of each individual protomer is preserved and interaction interfaces are formed by lipid-exposed surfaces. Although domain-swap models, i.e. models in which domains TM1–5 and TM6–7 would exchange between protomers, have also been proposed in the literature, there

Small molecules targeting GPCR oligomers

In view of the emerging evidence that GPCR heterodimers can generate very distinct signals from the corresponding homodimers (Milligan 2008), the development of small-molecule ligands that are specific for these complexes is attracting a great deal of attention as a potential new way to discover novel drugs with lesser side effects. Co-administration of conventional drugs targeting each of the two protomers in a GPCR dimer may result in limited therapeutic effect due to the potentially

Concluding remarks and outlook

Albeit challenging, targeting GPCR dimers/oligomers has generated a great deal of excitement about a new opportunity to discover more potent and selective drugs with lesser side effects. The wealth of new structural, biochemical, and biophysical information on GPCR monomers and dimers/oligomers that is recently appearing in the literature offers us a unique opportunity to build increasingly accurate computational models of GPCR complex systems. These models, eventually refined on the basis of

Acknowledgements

Our work on GPCR dimerization/oligomerization is supported by NIH grants DA017976, DA020032, and DA026434 from the National Institute on Drug Abuse. The author wishes to thank Dr. Andrea Bortolato for helping generate Fig. 1.

References (111)

  • KimS.K. et al.

    Computational prediction of homodimerization of the A3 adenosine receptor

    Journal of Molecular Graphics & Modeling

    (2006)
  • KlcoJ.M. et al.

    C5a receptor oligomerization. I. Disulfide trapping reveals oligomers and potential contact surfaces in a G protein-coupled receptor

    Journal of Biological Chemistry

    (2003)
  • LefkowitzR.J.

    Seven transmembrane receptors: A brief personal retrospective

    Biochemical and Biophysical Acta

    (2007)
  • LiJ. et al.

    Structure of bovine rhodopsin in a trigonal crystal form

    Journal of Molecular Biology

    (2004)
  • LiangY. et al.

    Rhodopsin signaling and organization in heterozygote rhodopsin knockout mice

    Journal of Biological Chemistry

    (2004)
  • LipinskiC.A. et al.

    Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings

    Advanced Drug Delivery Reviews

    (2001)
  • MilliganG.

    G-protein-coupled receptor heterodimers: Pharmacology, function and relevance to drug discovery

    Drug Discovery Today

    (2006)
  • NgG.Y. et al.

    Dopamine D2 receptor dimers and receptor-blocking peptides

    Biochemical and Biophysical Research Communications

    (1996)
  • OkadaT. et al.

    The retinal conformation and its environment in rhodopsin in light of a new 2.2 A crystal structure

    Journal of Molecular Biology

    (2004)
  • OvertonM.C. et al.

    Oligomerization, biogenesis, and signaling is promoted by a glycophorin A-like dimerization motif in transmembrane domain 1 of a yeast G protein-coupled receptor

    Journal of Biological Chemistry

    (2003)
  • PanettaR. et al.

    Physiological relevance of GPCR oligomerization and its impact on drug discovery

    Drug Discovery Today

    (2008)
  • PortogheseP.S. et al.

    Opioid agonist and antagonist bivalent ligands as receptor probes

    Life Sciences

    (1982)
  • SabioM. et al.

    Use of the X-ray structure of the beta2-adrenergic receptor for drug discovery. Part 2: Identification of active compounds

    Bioorganic Medicinal Chemistry Letters

    (2008)
  • SchertlerG.F.

    Structure of rhodopsin and the metarhodopsin I photointermediate

    Current Opinion in Structural Biology

    (2005)
  • ShimamuraT. et al.

    Crystal structure of squid rhodopsin with intracellularly extended cytoplasmic region

    Journal of Biological Chemistry

    (2008)
  • StanasilaL. et al.

    Oligomerization of the alpha 1a- and alpha 1b-adrenergic receptor subtypes. Potential implications in receptor internalization

    Journal of Biological Chemistry

    (2003)
  • StandfussJ. et al.

    Crystal structure of a thermally stable rhodopsin mutant

    Journal of Molecular Biology

    (2007)
  • TakemoriA.E. et al.

    Long-acting agonist and antagonist activities of naltrexamine bivalent ligands in mice

    European Journal of Pharmacology

    (1990)
  • TaylorM.S. et al.

    Mutations affecting the oligomerization interface of G-protein-coupled receptors revealed by a novel de novo protein design framework

    Biophysical Journal

    (2008)
  • AbdAllaS. et al.

    Increased AT(1) receptor heterodimers in preeclampsia mediate enhanced angiotensin II responsiveness

    Nature Medicine

    (2001)
  • AntonyJ. et al.

    Dualsteric GPCR targeting: A novel route to binding and signaling pathway selectivity

    FASEB Journal

    (2008)
  • BermanH.M. et al.

    The Protein Data Bank

    Nucleic Acids Research

    (2000)
  • Berque-BestelI. et al.

    Bivalent ligands as specific pharmacological tools for G protein-coupled receptor dimers

    Current Drug Discovery Technology

    (2008)
  • BlazerL.L. et al.

    Small molecule protein–protein interaction inhibitors as CNS therapeutic agents: Current progress and future hurdles

    Neuropsychopharmacology

    (2008)
  • BortolatoA. et al.

    Progress in Elucidating the Structural and Dynamic Character of G-Protein Coupled Receptor Oligomers for Use in Drug Discovery

    Current Pharmaceutical Design

    (2009)
  • CaputoG.A. et al.

    Computationally designed peptide inhibitors of protein–protein interactions in membranes

    Biochemistry

    (2008)
  • CarribaP. et al.

    Striatal adenosine A2A and cannabinoid CB1 receptors form functional heteromeric complexes that mediate the motor effects of cannabinoids

    Neuropsychopharmacology

    (2007)
  • CarrilloJ.J. et al.

    Multiple interactions between transmembrane helices generate the oligomeric alpha1b-adrenoceptor

    Molecular Pharmacology

    (2004)
  • ChabreM. et al.

    Biophysics: Is rhodopsin dimeric in native retinal rods?

    Nature

    (2003)
  • CherezovV. et al.

    High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor

    Science

    (2007)
  • CostanziS.

    On the applicability of GPCR homology models to computer-aided drug discovery: A comparison between in silico and crystal structures of the beta2-adrenergic receptor

    Journal of Medicinal Chemistry

    (2008)
  • DanielsD.J. et al.

    Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series

    Proceedings of the National Academy of Sciences of the United States of America

    (2005)
  • DrorR.O. et al.

    Identification of two distinct inactive conformations of the beta2-adrenergic receptor reconciles structural and biochemical observations

    Proceedings of the National Academy of Sciences of the United States of America

    (2009)
  • ErezM. et al.

    Narcotic antagonistic potency of bivalent ligands which contain beta-naltrexamine. Evidence for bridging between proximal recognition sites

    Journal of Medicinal Chemistry

    (1982)
  • FanelliF. et al.

    Inactive and active states and supramolecular organization of GPCRs: Insights from computational modeling

    Journal of Computer Aided Molecular Design

    (2006)
  • FilizolaM. et al.

    Oligomerization domains of G-protein coupled receptors: Insights into the structural basis of GPCR association

  • FilizolaM. et al.

    Prediction of heterodimerization interfaces of G-protein coupled receptors with a new subtractive correlated mutation method

    Protein Engineering

    (2002)
  • FilizolaM. et al.

    Structural models for dimerization of G-protein coupled receptors: The opioid receptor homodimers

    Biopolymers

    (2002)
  • FilizolaM. et al.

    The study of G-protein coupled receptor oligomerization with computational modeling and bioinformatics

    FEBS Journal

    (2005)
  • FotiadisD. et al.

    Atomic-force microscopy: Rhodopsin dimers in native disc membranes

    Nature

    (2003)
  • Cited by (0)

    View full text