Structural basis for the specific inhibition of heterotrimeric G^sub q^ protein by a small molecule

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-08, Vol.107 (31), p.13666
• Main Authors: Nishimura, Akiyuki, Kitano, Ken, Takasaki, Jun, Taniguchi, Masatoshi, Mizuno, Norikazu, Tago, Kenji, Hakoshima, Toshio, Itoh, Hiroshi
• Format: Article
• Language: English
• Subjects: Binding sites; Cells; Glycoproteins; Molecular structure; Signal transduction; T cell receptors
• ISSN: 0027-8424; 1091-6490

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 ...-selective inhibitor. YM-254890 specifically inhibits the GDP/GTP exchange reaction of α subunit of ... protein (...) by inhibiting the GDP release from ... X-ray crystal structure analysis of the ...- YM-254890 complex shows that YM-254890 binds the hydrophobic cleft between two interdomain linkers connecting the GTPase and helical domains of the ... 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 Ga subunit and an insight into the molecular mechanism of G protein activation. (ProQuest: ... denotes formulae/symbols omitted.)