Journal
STRUCTURE
Volume 13, Issue 7, Pages 1069-1080Publisher
CELL PRESS
DOI: 10.1016/j.str.2005.04.007
Keywords
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Funding
- NIGMS NIH HHS [P01 GM 065533, P01 GM065533, R01 GM062338, R01 GM 062338] Funding Source: Medline
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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 G alpha binding peptides. Herein, we report a GDP-selective G alpha binding peptide, KB-752, that enhances spontaneous nucleotide exchange of G alpha(i) subunits. Structural determination of the G alpha(i1)/peptide complex reveals unique changes in the Ga switch regions predicted to enhance nucleotide exchange by creating a GDP dissociation route. Our results cast light onto a potential mechanism by which G alpha subunits adopt a conformation suitable for nucleotide exchange.
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