Prediction of heterodimerization interfaces of G-protein coupled receptors with a new subtractive correlated mutation method
Reads0
Chats0
TLDR
The new subtractive correlated mutation method reveals likely heterodimerization interfaces amongst the different alternatives for the positioning of two tightly packed bundles of seven transmembrane domains next to each other in contact heterodimers of GPCRs.Abstract:
Recent studies employing differential epitope tagging, selective immunoprecipitation of receptor complexes and fluorescence or bioluminescence resonance energy transfer techniques provide direct evidence for heterodimerization between both closely and distantly related members of the G-protein coupled receptor (GPCR) family. Since heterodimerization appears to play a role in modulating agonist affinity, efficacy and/or trafficking properties, the molecular models of GPCRs required to understand receptor function must consider these oligomerization hypotheses. To advance knowledge in this field, we present here a computational approach based on correlated mutation analysis and the structural information contained in three-dimensional molecular models of the transmembrane regions of GPCRs built using the rhodopsin crystal structure as a template. The new subtractive correlated mutation method reveals likely heterodimerization interfaces amongst the different alternatives for the positioning of two tightly packed bundles of seven transmembrane domains next to each other in contact heterodimers of GPCRs. Predictions are applied to GPCRs in the class of opioid receptors. However, in the absence of a known structure of any GPCR dimer, the features of the method and predictions are also illustrated and analyzed for a dimeric complex of known structure.read more
Citations
More filters
Journal ArticleDOI
G Protein-Coupled Receptor Dimerization: Function and Ligand Pharmacology
TL;DR: Key questions that remain to be addressed effectively include the prevalence and relevance of these in native tissues and the implications of heterodimerization for pharmacology and, potentially, for drug design.
Journal ArticleDOI
Emerging role of homo- and heterodimerization in G-protein-coupled receptor biosynthesis and maturation
TL;DR: Increasing evidence suggests that homodimerization might have a similar role in the receptor maturation process for many GPCRs.
Journal ArticleDOI
The fourth transmembrane segment forms the interface of the dopamine D2 receptor homodimer.
TL;DR: By using cysteine cross-linking, the fourth transmembrane segment (TM4) is identified as a symmetrical dimer interface in the dopamine D2 receptor, suggesting that the receptor is a constitutive dimer.
Journal ArticleDOI
G Protein–Coupled Receptor Oligomerization: Implications for G Protein Activation and Cell Signaling
TL;DR: The mechanistic implications of GPCR dimerization and/or oligomerization on receptor activation and interactions with G proteins are explored and may provide novel and more selective sites for pharmacological tuning of cardiovascular function.
Journal ArticleDOI
Facilitation of μ-Opioid Receptor Activity by Preventing δ-Opioid Receptor-Mediated Codegradation
Shao Qiu He,Zhen Ning Zhang,Ji-Song Guan,Hong Rui Liu,Bo Zhao,Hai-Bo Wang,Qian Li,Hong Yang,Jie Luo,Zi Yan Li,Qiong Wang,Ying Jin Lu,Lan Bao,Xu Zhang +13 more
TL;DR: Dissociation of MORs from DORs in the cell membrane is a potential strategy to improve opioid analgesic therapies and is shown to enhance the morphine analgesia and reduce the antinociceptive tolerance to morphine.
References
More filters
Journal ArticleDOI
Crystal Structure of Rhodopsin: A G Protein-Coupled Receptor
Krzysztof Palczewski,Takashi Kumasaka,Tetsuya Hori,Craig A. Behnke,H. Motoshima,Brian A. Fox,I. Le Trong,David C. Teller,Tetsuji Okada,Ronald E. Stenkamp,Masaki Yamamoto,Masashi Miyano +11 more
TL;DR: This article determined the structure of rhodopsin from diffraction data extending to 2.8 angstroms resolution and found that the highly organized structure in the extracellular region, including a conserved disulfide bridge, forms a basis for the arrangement of the sevenhelix transmembrane motif.
Journal ArticleDOI
Heterodimerization is required for the formation of a functional GABAB receptor
Julia Helen Margaret White,Alan Wise,Martin J. Main,Andrew Green,Neil J. Fraser,Graham H. Disney,Ashley A. Barnes,Piers C. Emson,Steven M. Foord,Fiona H. Marshall +9 more
TL;DR: The cloning of a complementary DNA encoding a new subtype of the GABAB receptor (GABABR2), which is identified by mining expressed-sequence-tag databases, indicates that, in vivo, functional brain GABAB receptors may be heterodimers composed of GABABR1 and GABABR2.
Journal ArticleDOI
Gabab-receptor subtypes assemble into functional heteromeric complexes
Klemens Kaupmann,Barbara Malitschek,Valerie Schuler,Jakob Heid,Wolfgang Froestl,Pascal Beck,Johannes Mosbacher,Serge Bischoff,Ákos Kulik,Ryuichi Shigemoto,Andreas Karschin,Bernhard Bettler +11 more
TL;DR: A new GABAB receptor subtype is described, GABABR2, which does not bind available GABAB antagonists with measurable potency and exhibits a significant increase in agonist- and partial-agonist-binding potencies as compared with individual receptors.
Journal ArticleDOI
G-protein-coupled receptor heterodimerization modulates receptor function
Bryen A. Jordan,Lakshmi A. Devi +1 more
TL;DR: In this article, the authors provide biochemical and pharmacological evidence for the heterodimerization of two fully functional opioid receptors, κ and δ, which results in a new receptor that exhibits ligand binding and functional properties that are distinct from those of either receptor.
Journal ArticleDOI
GABA(B) receptors function as a heteromeric assembly of the subunits GABA(B)R1 and GABA(B)R2
Kenneth A. Jones,Beth E. Borowsky,Joe A. Tamm,Douglas A. Craig,Margaret M. Durkin,Meng Dai,Wen-Jeng Yao,Mary C. Johnson,Caryn A Gunwaldsen,Ling-Yan Huang,Cheng Tang,Quanrong Shen,John Salon,Kelley L. Morse,Thomas M. Laz,Kelli E. Smith,Dhanapalan Nagarathnam,Stewart A. Noble,Theresa Branchek,Christophe P. G. Gerald +19 more
TL;DR: It is shown that co-expression of two GPCR structures, GABABR1 and GABABR2, belonging to the samesubfamily is essential for signal transduction by GABAB receptors.