Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase gamma - PubMed (original) (raw)
Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase gamma
M E Pacold et al. Cell. 2000.
Free article
Abstract
Ras activation of phosphoinositide 3-kinase (PI3K) is important for survival of transformed cells. We find that PI3Kgamma is strongly and directly activated by H-Ras G12V in vivo or by GTPgammaS-loaded H-Ras in vitro. We have determined a crystal structure of a PI3Kgamma/Ras.GMPPNP complex. A critical loop in the Ras binding domain positions Ras so that it uses its switch I and switch II regions to bind PI3Kgamma. Mutagenesis shows that interactions with both regions are essential for binding PI3Kgamma. Ras also forms a direct contact with the PI3Kgamma catalytic domain. These unique Ras/PI3Kgamma interactions are likely to be shared by PI3Kalpha. The complex with Ras shows a change in the PI3K conformation that may represent an allosteric component of Ras activation.
Similar articles
- Biophysical and Structural Characterization of Novel RAS-Binding Domains (RBDs) of PI3Kα and PI3Kγ.
Martinez NG, Thieker DF, Carey LM, Rasquinha JA, Kistler SK, Kuhlman BA, Campbell SL. Martinez NG, et al. J Mol Biol. 2021 Apr 16;433(8):166838. doi: 10.1016/j.jmb.2021.166838. Epub 2021 Feb 1. J Mol Biol. 2021. PMID: 33539876 Free PMC article. - Activation of phosphoinositide 3-kinase gamma by Ras.
Suire S, Hawkins P, Stephens L. Suire S, et al. Curr Biol. 2002 Jul 9;12(13):1068-75. doi: 10.1016/s0960-9822(02)00933-8. Curr Biol. 2002. PMID: 12121613 - Interaction of Ras with phosphoinositide 3-kinase gamma.
Rubio I, Rodriguez-Viciana P, Downward J, Wetzker R. Rubio I, et al. Biochem J. 1997 Sep 15;326 ( Pt 3)(Pt 3):891-5. doi: 10.1042/bj3260891. Biochem J. 1997. PMID: 9307042 Free PMC article. - PI3K class IB pathway in neutrophils.
Andrews S, Stephens LR, Hawkins PT. Andrews S, et al. Sci STKE. 2007 Oct 9;2007(407):cm3. doi: 10.1126/stke.4072007cm3. Sci STKE. 2007. PMID: 17925574 Review. - Structural comparisons of class I phosphoinositide 3-kinases.
Amzel LM, Huang CH, Mandelker D, Lengauer C, Gabelli SB, Vogelstein B. Amzel LM, et al. Nat Rev Cancer. 2008 Sep;8(9):665-9. doi: 10.1038/nrc2443. Nat Rev Cancer. 2008. PMID: 18633356 Free PMC article. Review.
Cited by
- Spatiotemporal dynamics of membrane surface charge regulates cell polarity and migration.
Banerjee T, Biswas D, Pal DS, Miao Y, Iglesias PA, Devreotes PN. Banerjee T, et al. Nat Cell Biol. 2022 Oct;24(10):1499-1515. doi: 10.1038/s41556-022-00997-7. Epub 2022 Oct 6. Nat Cell Biol. 2022. PMID: 36202973 Free PMC article. - PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting.
Thorpe LM, Yuzugullu H, Zhao JJ. Thorpe LM, et al. Nat Rev Cancer. 2015 Jan;15(1):7-24. doi: 10.1038/nrc3860. Nat Rev Cancer. 2015. PMID: 25533673 Free PMC article. Review. - In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction.
Shima F, Yoshikawa Y, Ye M, Araki M, Matsumoto S, Liao J, Hu L, Sugimoto T, Ijiri Y, Takeda A, Nishiyama Y, Sato C, Muraoka S, Tamura A, Osoda T, Tsuda K, Miyakawa T, Fukunishi H, Shimada J, Kumasaka T, Yamamoto M, Kataoka T. Shima F, et al. Proc Natl Acad Sci U S A. 2013 May 14;110(20):8182-7. doi: 10.1073/pnas.1217730110. Epub 2013 Apr 29. Proc Natl Acad Sci U S A. 2013. PMID: 23630290 Free PMC article. - The orchestrated signaling by PI3Kα and PTEN at the membrane interface.
Kotzampasi DM, Premeti K, Papafotika A, Syropoulou V, Christoforidis S, Cournia Z, Leondaritis G. Kotzampasi DM, et al. Comput Struct Biotechnol J. 2022 Oct 7;20:5607-5621. doi: 10.1016/j.csbj.2022.10.007. eCollection 2022. Comput Struct Biotechnol J. 2022. PMID: 36284707 Free PMC article. Review. - From bench to bedside: current development and emerging trend of KRAS-targeted therapy.
Chen Y, Liu QP, Xie H, Ding J. Chen Y, et al. Acta Pharmacol Sin. 2024 Apr;45(4):686-703. doi: 10.1038/s41401-023-01194-4. Epub 2023 Dec 4. Acta Pharmacol Sin. 2024. PMID: 38049578 Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Research Materials
Miscellaneous