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Biochemistry. 2017 Oct 24;56(42):5628-5634. doi: 10.1021/acs.biochem.7b00747. Epub 2017 Oct 10.

Structural Basis for G Protein-Coupled Receptor Activation.

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Department of Pharmaceutical Chemistry, University of California, San Francisco , San Francisco, California 94158, United States.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School , Boston, Massachusetts 02115, United States.


G protein-coupled receptors (GPCRs) are critical regulators of human physiology and make up the largest single class of therapeutic drug targets. Although GPCRs regulate highly diverse physiology, they share a common signaling mechanism whereby extracellular stimuli induce conformational changes in the receptor that enable activation of heterotrimeric G proteins and other intracellular effectors. Advances in GPCR structural biology have made it possible to examine ligand-induced GPCR activation at an unprecedented level of detail. Here, we review the structural basis for family A GPCR activation, with a focus on GPCRs for which structures are available in both active or active-like states and inactive states. Crystallographic and other biophysical data show how chemically diverse ligands stabilize highly conserved conformational changes on the intracellular side of the receptors, allowing many different extracellular stimuli to utilize shared downstream signaling molecules. Finally, we discuss the remaining challenges in understanding GPCR activation and signaling and highlight new technologies that may allow unanswered questions to be resolved.

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