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G Protein-Coupled Receptors: Conformational “Gatekeepers” of Transmembrane Signal Transduction and Diversification

Abrol, Ravinder and Goddard, William A., III (2011) G Protein-Coupled Receptors: Conformational “Gatekeepers” of Transmembrane Signal Transduction and Diversification. In: Extracellular and Intracellular Signaling. RSC drug discovery series. No.10. Royal Society of Chemistry , Cambridge, pp. 188-229. ISBN 978-1-84973-160-7.

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Proteins in the cellular signaling machinery accomplish an amazing spectrum of functions necessary for the growth and survival of life by a network of signaling events separated in both space and time. Membrane proteins enable signal transduction across the cell membrane, which results in these signaling events inside the cell leading to a physiological response. G protein-coupled receptors (GPCRs) form the largest family of membrane proteins that process a very diverse set of extracellular signals and are capable of transducing multiple intracellular signaling pathways, mediated by G proteins and/or Arrestins, each with potentially different functional consequences. This “pleiotropic” nature of GPCRs is enabled by a high conformational flexibility of GPCRs, which allows for a unique ensemble of possible conformations depending on the state of the GPCR, whether it is in the apo form, or interacting with a ligand/antibody, or interacting with another protein. Each ligand can induce a different set of conformations in a GPCR, which can interact with G protein and Arrestin pathways in different ways, resulting in different physiological outcomes. This chapter provides an overview of how GPCRs use their conformational flexibility to perform a complex array of functions and how this can be used advantageously to bias signaling within the cell. A detailed understanding of the signaling pathways that are turned on by GPCRs, combined with the development of biased agonists and allosteric modulators to select specific outcomes, provides a promising avenue for developing therapeutics with minimal side-effects.

Item Type:Book Section
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Abrol, Ravinder0000-0001-7333-6793
Goddard, William A., III0000-0003-0097-5716
Additional Information:© 2011 Royal Society of Chemistry. Our development of predictive methods for structures and function of GPCR started around 1998 with an ARO-MURI grant oriented toward olfaction, a time when no 3D structures were available. The early advances were led by Dr. N. Vaidehi (now Professor of Immunology at City of Hope, Duarte, California) and Wely Floriano (now Associate Professor of Chemistry at Lakehead University, Ontario, Canada). Other important early contributions were made by Deqiang Zhang, Spencer Hall, Peter Freddolino, Eun Jung Choi, Georgios Zamanakos, Peter Kekenes-Huskey, Peter Freddolino, Yashar Kalani, Rene Trabanino, Victor Kam, Art Cho, John Wendel, P. Hummel, Peter Spijker; Joyce Yao-chun Peng, Youyong Li and Jiyoung Heo. More recently the team has been led by Ravinder Abrol, with major contributions from Jenelle Bray, Soo-Kyung Kim, Bartosz Trzaskowski, Adam Griffith, Caitlin Scott, Caglar Tanrikulu and Andrea Kirkpatrick. The funding sources that have allowed us to continue this project came from Sanofi Aventis, Boehringer-Ingelheim, Pfizer, Schering AG, PharmSelex and from NIH (R21-MH073910-01-A1, NIH 1 RO1 CA 112293-01, NIH 1R01 GM62523-01, NIH R01 AI40567).
Funding AgencyGrant Number
NIHRO1 CA 112293-01
NIHR01 GM62523-01
NIHR01 AI40567
Army Research Office (ARO)UNSPECIFIED
Series Name:RSC drug discovery series
Issue or Number:10
Record Number:CaltechAUTHORS:20160801-124351119
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:69355
Deposited By: Tony Diaz
Deposited On:01 Aug 2016 19:52
Last Modified:03 Oct 2019 10:21

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