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First published on April 12, 2007; DOI: 10.1124/mol.107.034348

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Received for publication January 22, 2007.
Revised March 25, 2007.
Accepted for publication April 10, 2007.

Receptor-Mediated Activation of Heterotrimeric G-proteins: Current Structural Insights

Christopher A. Johnston 1 David P. Siderovski 1*

1 UNC-Chapel Hill School of Medicine

* Address correspondence to: E-mail: dsiderov{at}med.unc.edu

Abstract

G protein-coupled receptors (GPCRs) serve as catalytic activators of heterotrimeric G-proteins (G{alpha}{beta}{gamma}) by exchanging GTP for the bound GDP on the G{alpha} subunit. This guanine nucleotide exchange factor (GEF) activity of GPCRs is the initial step in the G-protein cycle and determines the onset of various intracellular signaling pathways that govern critical physiological responses to extracellular cues. Although the structural basis for many steps in the G-protein nucleotide cycle have been made clear over the past decade, the precise mechanism for receptor-mediated G-protein activation remains incompletely defined. As these receptors have historically represented a set of rich drug targets, more complete understanding of their mechanism of action should provide further avenues for drug discovery. Currently, several models have been proposed to explain the communication between activated GPCRs and G{alpha}{beta}{gamma} leading to the structural changes required for guanine nucleotide exchange. This review is focused on the structural biology of G-protein signal transduction with an emphasis on the current hypotheses regarding G{alpha}{beta}{gamma} activation. We highlight several recent results shedding new light on the structural changes in G{alpha} that may underlie GDP release.


Key words: Dopamine, Gi family, Gs family, G protein regulation, Structure determinations, Phage display, X-ray crystallography


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