MinireviewIncreasingly accurate dynamic molecular models of G-protein coupled receptor oligomers: Panacea or Pandora's box for novel drug discovery?
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)
- et al.
Integrated methods for the construction of three-dimensional models and computational probing of structure–function relations in G protein-coupled receptors
- et al.
Two transmembrane Cys residues are involved in 5-HT4 receptor dimerization
Biochemical and Biophysical Research Communication
(2007) - et al.
GPCR-jacking: From a new route in RTK signalling to a new concept in GPCR activation
Trends in Pharmacological Sciences
(2007) Dimerization of the lutropin receptor: Insights from computational modeling
Molecular and Cellular Endocrinology
(2007)- et al.
Bi-directional heterologous desensitization between the major HIV-1 co-receptor CXCR4 and the kappa-opioid receptor
Journal of Neuroimmunology
(2008) - et al.
On the accuracy of homology modeling and sequence alignment methods applied to membrane proteins
Biophysical Journal
(2006) - et al.
Oligomerization of the yeast alpha-factor receptor: Implications for dominant negative effects of mutant receptors
Journal of Biological Chemistry
(2006) - et al.
The fourth transmembrane segment forms the interface of the dopamine D2 receptor homodimer
Journal of Biological Chemistry
(2003) - et al.
A specific cholesterol binding site is established by the 2.8 A structure of the human beta2-adrenergic receptor
Structure
(2008) - et al.
A peptide derived from a beta2-adrenergic receptor transmembrane domain inhibits both receptor dimerization and activation
Journal of Biological Chemistry
(1996)