Journal ArticleDOI
Emerging paradigms in GPCR allostery: implications for drug discovery
Reads0
Chats0
TLDR
New findings have the potential to alter how screening for allosteric drugs is performed and may increase the chances of success in the development ofallosteric modulators as clinical lead compounds.Abstract:
Allosteric ligands bind to G protein-coupled receptors (GPCRs; also known as seven-transmembrane receptors) at sites that are distinct from the sites to which endogenous ligands bind. The existence of allosteric ligands has enriched the ways in which the functions of GPCRs can be manipulated for potential therapeutic benefit, yet the complexity of their actions provides both challenges and opportunities for drug screening and development. Converging avenues of research in areas such as biased signalling by allosteric ligands and the mechanisms by which allosteric ligands modulate the effects of diverse endogenous ligands have provided new insights into how interactions between allosteric ligands and GPCRs could be exploited for drug discovery. These new findings have the potential to alter how screening for allosteric drugs is performed and may increase the chances of success in the development of allosteric modulators as clinical lead compounds.read more
Citations
More filters
Journal ArticleDOI
International Union of Basic and Clinical Pharmacology. CXII: Adenosine Receptors: A Further Update
Adriaan P. IJzerman,Kenneth A. Jacobson,Christa E. Müller,Bruce N. Cronstein,Rodrigo A. Cunha +4 more
TL;DR: Adenosine receptors (ARs) are of continuing interest for future treatment of chronic and acute disease conditions, including inflammatory diseases, neurodegenerative afflictions, and cancer.
Journal ArticleDOI
Effect of Novel Allosteric Modulators of Metabotropic Glutamate Receptors on Drug Self-administration and Relapse: A Review of Preclinical Studies and Their Clinical Implications.
TL;DR: Results from recent studies of systemically injected PAMs and NAMs of mGluRs in rodents and monkeys are reviewed, focusing on whether they reduce drug self-administration, reinstatement of drug seeking, and incubation of drug craving.
Journal ArticleDOI
AlloMAPS: allosteric mutation analysis and polymorphism of signaling database.
Zhen Wah Tan,Wei-Ven Tee,Wei-Ven Tee,Enrico Guarnera,Lauren N. Booth,Lauren N. Booth,Igor N. Berezovsky,Igor N. Berezovsky +7 more
TL;DR: The AlloMAPS database provides data on the causality and energetics of allosteric communication obtained with the structure-based statistical mechanical model of allostery (SBSMMA) and is proposed to be used for evaluating the effects ofallosteric signaling in the search for latent regulatory sites and in the design ofAllosteric sites and effectors.
Journal ArticleDOI
Novel Mechanism of Voltage-Gated N-type (Cav2.2) Calcium Channel Inhibition Revealed through α-Conotoxin Vc1.1 Activation of the GABAB Receptor
TL;DR: A novel mechanism by which Vc1.1 activates GABABR and requires the GABAB1a proximal carboxyl terminus domain to inhibit Cav2.2 channels is proposed, which provides important insights into how GABABRs mediate Cav 2.2 channel inhibition and alter nociceptive transmission.
Journal ArticleDOI
Endogenous vs Exogenous Allosteric Modulators in GPCRs: A dispute for shuttling CB1 among different membrane microenvironments.
Mariano Stornaiuolo,Agostino Bruno,Lorenzo Botta,Giuseppe La Regina,Sandro Cosconati,Romano Silvestri,Luciana Marinelli,Ettore Novellino +7 more
TL;DR: A Cannabinoid Receptor 1 (CB1) binding site for the selective allosteric modulator ORG27569 is here identified through an integrate approach of consensus pocket prediction, mutagenesis studies and Mass Spectrometry, which presents the structural features of a Cholesterol Consensus Motif.
References
More filters
Journal ArticleDOI
International Union of Pharmacology: Approaches to the Nomenclature of Voltage-Gated Ion Channels
William A. Catterall,K. G. Chandy,David E. Clapham,George A. Gutman,Franz Hofmann,Anthony J. Harmar,Darrell R. Abernethy,Michael Spedding +7 more
TL;DR: This issue of Pharmacological Reviews includes a new venture in the collaboration between the International Union of Pharmacology (IUPHAR) and the American Society for Pharmacology and Experimental Therapeutics (ASPET), in that a new classification of voltage-gated ion channels is outlined.
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
Crystal structure of the β2 adrenergic receptor-Gs protein complex.
Søren G. F. Rasmussen,Brian T. DeVree,Yaozhong Zou,Andrew C. Kruse,Ka Young Chung,Tong Sun Kobilka,Foon Sun Thian,Pil Seok Chae,Els Pardon,Els Pardon,Diane M. Calinski,Jesper Mosolff Mathiesen,Syed T. A. Shah,Joseph A. Lyons,Martin Caffrey,Samuel H. Gellman,Jan Steyaert,Jan Steyaert,Georgios Skiniotis,William I. Weis,Roger K. Sunahara,Brian K. Kobilka +21 more
TL;DR: This crystal structure represents the first high-resolution view of transmembrane signalling by a GPCR and the most surprising observation is a major displacement of the α-helical domain of Gαs relative to the Ras-like GTPase domain.
Journal ArticleDOI
The Many Roles of Chemokines and Chemokine Receptors in Inflammation
TL;DR: The properties of chemokines and their receptors are discussed and the roles of these chemoattractants in selected clinical disorders are highlighted.
Journal ArticleDOI
Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists.
Beili Wu,Ellen Y.T. Chien,Clifford D. Mol,Gustavo Fenalti,Wei Liu,Vsevolod Katritch,Ruben Abagyan,Alexei Brooun,Peter A. Wells,F. Christopher Bi,Damon J. Hamel,Peter Kuhn,Tracy M. Handel,Vadim Cherezov,Raymond C. Stevens +14 more
TL;DR: Five independent crystal structures of CXCR4 bound to an antagonist small molecule IT1t and a cyclic peptide CVX15 at 2.5 to 3.2 angstrom resolution reveal a consistent homodimer with an interface including helices V and VI that may be involved in regulating signaling.
Related Papers (5)
Activation and allosteric modulation of a muscarinic acetylcholine receptor
Crystal structure of the β2 adrenergic receptor-Gs protein complex.
Søren G. F. Rasmussen,Brian T. DeVree,Yaozhong Zou,Andrew C. Kruse,Ka Young Chung,Tong Sun Kobilka,Foon Sun Thian,Pil Seok Chae,Els Pardon,Els Pardon,Diane M. Calinski,Jesper Mosolff Mathiesen,Syed T. A. Shah,Joseph A. Lyons,Martin Caffrey,Samuel H. Gellman,Jan Steyaert,Jan Steyaert,Georgios Skiniotis,William I. Weis,Roger K. Sunahara,Brian K. Kobilka +21 more