title: Structural basis for the specific inhibition of heterotrimeric Gq protein by a small molecule.
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 Gq-selective inhibitor. YM-254890 specifically inhibits the GDP/GTP exchange reaction of alpha subunit of Gq protein (Galphaq) by inhibiting the GDP release from Galphaq. X-ray crystal structure analysis of the Galphaqbetagamma-YM-254890 complex shows that YM-254890 binds the hydrophobic cleft between two interdomain linkers connecting the GTPase and helical domains of the Galphaq. 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 Galpha subunit and an insight into the molecular mechanism of G protein activation.
authors.affiliation: Signal Transduction Laboratory, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan.
authors.forename: Akiyuki
authors.initials: A
authors.lastname: Nishimura
authors.forename: Ken
authors.initials: K
authors.lastname: Kitano
authors.forename: Jun
authors.initials: J
authors.lastname: Takasaki
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Norikazu
authors.initials: N
authors.lastname: Mizuno
authors.forename: Kenji
authors.initials: K
authors.lastname: Tago
authors.forename: Toshio
authors.initials: T
authors.lastname: Hakoshima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
chemical_list: D010456:Peptides, Cyclic; C475455:YM-254890; D043802:GTP-Binding Protein alpha Subunits, Gq-G11