Structural basis for the specific inhibition of heterotrimeric Gqprotein by a small molecule

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-08, Vol.107 (31), p.13666-13671
• Main Authors: Nishimura, Akiyuki, Kitano, Ken, Takasaki, Jun, Taniguchi, Masatoshi, Mizuno, Norikazu, Tago, Kenji, Hakoshima, Toshio, Itoh, Hiroshi, Gilman, Alfred G.
• Format: Article
• Language: English
• Subjects: Cells; Crystal structure; Crystallization; Drug interactions; Gross domestic product; Hydrogen bonds; Molecules; Nucleotides; Proteins; Receptors
• ISSN: 0027-8424

Heterotrimeric GTP-binding proteins (G proteins) transmit extracellular stimuli perceived by G protein-coupled receptors (GPCRs) to intracellular signaling cascades. Hundreds of GPCRs exist in humans and are the targets of a large percentage of the pharmaceutical drugs used today. Because G proteins are regulated by GPCRs, small molecules that directly modulate G proteins have the potential to become therapeutic agents. However, strategies to develop modulators have been hampered by a lack of structural knowledge of targeting sites for specific modulator binding. Here we present the mechanism of action of the cyclic depsipeptide YM-254890, which is a recently discovered G q -selective inhibitor. YM-254890 specifically inhibits the GDP/GTP exchange reaction of α subunit of G q protein (Gα q ) by inhibiting the GDP release from Gα q . X-ray crystal structure analysis of the Gα q βγ–YM-254890 complex shows that YM-254890 binds the hydrophobic cleft between two interdomain linkers connecting the GTPase and helical domains of the Gα q . The binding stabilizes an inactive GDP-bound form through direct interactions with switch I and impairs the linker flexibility. Our studies provide a novel targeting site for the development of small molecules that selectively inhibit each Gα subunit and an insight into the molecular mechanism of G protein activation.