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

Akiyuki Nishimura, Ken Kitano, Jun Takasaki, Masatoshi Taniguchi, Norikazu Mizuno, Kenji Tago, Toshio Hakoshima, Hiroshi Itoh

Research output: Contribution to journalArticle

98 Citations (Scopus)

Abstract

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 Gq protein (Gαq) by inhibiting the GDP release from Gαq. X-ray crystal structure analysis of the Gαqβγ-YM- 254890 complex shows that YM-254890 binds the hydrophobic cleft between two interdomain linkers connecting the GTPase and helical domains of the Gαq. 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.

Original languageEnglish
Pages (from-to)13666-13671
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number31
DOIs
Publication statusPublished - Aug 3 2010
Externally publishedYes

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Heterotrimeric GTP-Binding Proteins
GTP-Binding Proteins
G-Protein-Coupled Receptors
Gq-G11 GTP-Binding Protein alpha Subunits
Depsipeptides
GTP Phosphohydrolases
Guanosine Triphosphate
Pharmaceutical Preparations
X-Rays
YM-254890
Therapeutics

All Science Journal Classification (ASJC) codes

  • General

Cite this

Structural basis for the specific inhibition of heterotrimeric G q protein by a small molecule. / Nishimura, Akiyuki; Kitano, Ken; Takasaki, Jun; Taniguchi, Masatoshi; Mizuno, Norikazu; Tago, Kenji; Hakoshima, Toshio; Itoh, Hiroshi.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 31, 03.08.2010, p. 13666-13671.

Research output: Contribution to journalArticle

Nishimura, Akiyuki ; Kitano, Ken ; Takasaki, Jun ; Taniguchi, Masatoshi ; Mizuno, Norikazu ; Tago, Kenji ; Hakoshima, Toshio ; Itoh, Hiroshi. / Structural basis for the specific inhibition of heterotrimeric G q protein by a small molecule. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 31. pp. 13666-13671.
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