3AH8

Structure of heterotrimeric G protein Galpha-q beta gamma in complex with an inhibitor YM-254890

Summary for 3AH8

• Entry DOI: 10.2210/pdb3ah8/pdb
• Related PRD ID: PRD_000482
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-1/Guanine nucleotide-binding protein G(q) subunit alpha chimeric protein, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (5 entities in total)
• Functional Keywords: heterotrimeric g protein, gtpase, galpha-q, gbeta, ggamma, inhibitor, ym-254890, signaling protein, signaling protein-inhibitor complex, signaling protein/inhibitor
• Biological source: Rattus norvegicus (Rat, Mouse); More
• Cellular location: Nucleus : P21279; Cell membrane ; Lipid-anchor ; Cytoplasmic side : P63212
• Total number of polymer chains: 4
• Total formula weight: 88842.15

Authors

Nishimura, A.,Kitano, K.,Takasaki, J.,Taniguchi, M.,Mizuno, N.,Tago, K.,Hakoshima, T.,Itoh, H. (deposition date: 2010-04-20, release date: 2010-07-21, Last modification date: 2023-11-15)

Primary citation

Nishimura, A.,Kitano, K.,Takasaki, J.,Taniguchi, M.,Mizuno, N.,Tago, K.,Hakoshima, T.,Itoh, H.
Structural basis for the specific inhibition of heterotrimeric Gq protein by a small molecule.
Proc.Natl.Acad.Sci.USA, 107:13666-13671, 2010

PubMed 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.

PubMed: 20639466
DOI: 10.1073/pnas.1003553107

Experimental method

X-RAY DIFFRACTION (2.9 Å)