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Title: Capitalizing on tumor genotyping: Towards the design of mutation specific inhibitors of phosphoinsitide-3-kinase

Abstract

PI3Ks catalyze the phosphorylation of the inositol hydroxyls of phosphoinositide membrane components. The changes in phosphorylation of the inositides recruit proteins to the plasma membrane that initiate important signaling cascades. PI3K{alpha}, one of the class IA PI3Ks, is highly mutated in cancers. All mutations analyzed result in an increase in enzymatic activity. The structures of this enzyme determined by X-ray diffraction, provide a framework for analyzing the possible structural effect of these mutations and their effect on the enzymatic activity. Many of the mutations occur at domain interfaces where they can affect domain interactions and relieve the inhibition of the wild-type enzyme by the nSH2 domain of p85. This mechanism is analogous to the mechanism of physiological activation by activated tyrosine-kinase receptors in which the phosphorylated tyrosine of the receptor (or their substrates) dislodges the nSH2 from its inhibitory position in the complex by competing with its binding to a loop in the helical domain. Other mutations in the kinase domain can directly affect the conformation of the catalytic site. One mutation, His1047Arg, uses a completely different mechanism: it changes the conformation of the C-terminal loop in such a way that it increases the interaction of the enzyme with themore » membrane, granting increased access to the phosphoinositide substrates. Taking advantage of the reliance of some cancers on the increased activity of mutated PI3K{alpha}, will require the development of isoform-specific, mutant-specific inhibitors. The structural, biochemical and physiological data that are becoming available for PI3Ks are an important first step in this direction.« less

Authors:
; ; ;  [1]
  1. JHU
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1019137
Resource Type:
Journal Article
Journal Name:
Adv. Enzyme Regul.
Additional Journal Information:
Journal Volume: 51; Journal Issue: (1) ; 2011
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; DESIGN; ENZYMES; INOSITOL; MEMBRANES; MUTATIONS; NEOPLASMS; PHOSPHORYLATION; PHOSPHOTRANSFERASES; PLASMA; PROTEINS; SUBSTRATES; TYROSINE; X-RAY DIFFRACTION

Citation Formats

Gabelli, Sandra B, Duong-Ly, Krisna C, Brower, Evan T, and Amzel, L Mario. Capitalizing on tumor genotyping: Towards the design of mutation specific inhibitors of phosphoinsitide-3-kinase. United States: N. p., 2011. Web. doi:10.1016/j.advenzreg.2010.09.013.
Gabelli, Sandra B, Duong-Ly, Krisna C, Brower, Evan T, & Amzel, L Mario. Capitalizing on tumor genotyping: Towards the design of mutation specific inhibitors of phosphoinsitide-3-kinase. United States. https://doi.org/10.1016/j.advenzreg.2010.09.013
Gabelli, Sandra B, Duong-Ly, Krisna C, Brower, Evan T, and Amzel, L Mario. 2011. "Capitalizing on tumor genotyping: Towards the design of mutation specific inhibitors of phosphoinsitide-3-kinase". United States. https://doi.org/10.1016/j.advenzreg.2010.09.013.
@article{osti_1019137,
title = {Capitalizing on tumor genotyping: Towards the design of mutation specific inhibitors of phosphoinsitide-3-kinase},
author = {Gabelli, Sandra B and Duong-Ly, Krisna C and Brower, Evan T and Amzel, L Mario},
abstractNote = {PI3Ks catalyze the phosphorylation of the inositol hydroxyls of phosphoinositide membrane components. The changes in phosphorylation of the inositides recruit proteins to the plasma membrane that initiate important signaling cascades. PI3K{alpha}, one of the class IA PI3Ks, is highly mutated in cancers. All mutations analyzed result in an increase in enzymatic activity. The structures of this enzyme determined by X-ray diffraction, provide a framework for analyzing the possible structural effect of these mutations and their effect on the enzymatic activity. Many of the mutations occur at domain interfaces where they can affect domain interactions and relieve the inhibition of the wild-type enzyme by the nSH2 domain of p85. This mechanism is analogous to the mechanism of physiological activation by activated tyrosine-kinase receptors in which the phosphorylated tyrosine of the receptor (or their substrates) dislodges the nSH2 from its inhibitory position in the complex by competing with its binding to a loop in the helical domain. Other mutations in the kinase domain can directly affect the conformation of the catalytic site. One mutation, His1047Arg, uses a completely different mechanism: it changes the conformation of the C-terminal loop in such a way that it increases the interaction of the enzyme with the membrane, granting increased access to the phosphoinositide substrates. Taking advantage of the reliance of some cancers on the increased activity of mutated PI3K{alpha}, will require the development of isoform-specific, mutant-specific inhibitors. The structural, biochemical and physiological data that are becoming available for PI3Ks are an important first step in this direction.},
doi = {10.1016/j.advenzreg.2010.09.013},
url = {https://www.osti.gov/biblio/1019137}, journal = {Adv. Enzyme Regul.},
number = (1) ; 2011,
volume = 51,
place = {United States},
year = {Tue Sep 06 00:00:00 EDT 2011},
month = {Tue Sep 06 00:00:00 EDT 2011}
}