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Structure of Galpha(i1) bound to a GDP-selective peptide provides insight into guanine nucleotide exchange.


ABSTRACT: Heterotrimeric G proteins are molecular switches that regulate numerous signaling pathways involved in cellular physiology. This characteristic is achieved by the adoption of two principal states: an inactive, GDP bound state and an active, GTP bound state. Under basal conditions, G proteins exist in the inactive, GDP bound state; thus, nucleotide exchange is crucial to the onset of signaling. Despite our understanding of G protein signaling pathways, the mechanism of nucleotide exchange remains elusive. We employed phage display technology to identify nucleotide state-dependent Galpha binding peptides. Herein, we report a GDP-selective Galpha binding peptide, KB-752, that enhances spontaneous nucleotide exchange of Galpha(i) subunits. Structural determination of the Galpha(i1)/peptide complex reveals unique changes in the Galpha switch regions predicted to enhance nucleotide exchange by creating a GDP dissociation route. Our results cast light onto a potential mechanism by which Galpha subunits adopt a conformation suitable for nucleotide exchange.

SUBMITTER: Johnston CA 

PROVIDER: S-EPMC1405235 | biostudies-literature | 2005 Jul

REPOSITORIES: biostudies-literature

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Structure of Galpha(i1) bound to a GDP-selective peptide provides insight into guanine nucleotide exchange.

Johnston Christopher A CA   Willard Francis S FS   Jezyk Mark R MR   Fredericks Zoey Z   Bodor Erik T ET   Jones Miller B MB   Blaesius Rainer R   Watts Val J VJ   Harden T Kendall TK   Sondek John J   Ramer J Kevin JK   Siderovski David P DP  

Structure (London, England : 1993) 20050701 7


Heterotrimeric G proteins are molecular switches that regulate numerous signaling pathways involved in cellular physiology. This characteristic is achieved by the adoption of two principal states: an inactive, GDP bound state and an active, GTP bound state. Under basal conditions, G proteins exist in the inactive, GDP bound state; thus, nucleotide exchange is crucial to the onset of signaling. Despite our understanding of G protein signaling pathways, the mechanism of nucleotide exchange remains  ...[more]

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