Structure of Gαi1 bound to a GDP-selective peptide provides insight into guanine nucleotide exchange

Christopher A. Johnston, Francis S. Willard, Mark R. Jezyk, Zoey Fredericks, Erik T. Bodor, Miller B. Jones, Rainer Blaesius, Val J. Watts, T. Kendall Harden, John Sondek, J. Kevin Ramer, David P. Siderovski

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


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 Gα binding peptides. Herein, we report a GDP-selective Gα binding peptide, KB-752, that enhances spontaneous nucleotide exchange of Gαi subunits. Structural determination of the Gαi1/peptide complex reveals unique changes in the Gα switch regions predicted to enhance nucleotide exchange by creating a GDP dissociation route. Our results cast light onto a potential mechanism by which Gα subunits adopt a conformation suitable for nucleotide exchange.

Original languageEnglish
Pages (from-to)1069-1080
Number of pages12
Issue number7
StatePublished - Jul 2005


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