期刊
BIOCHEMICAL JOURNAL
卷 444, 期 -, 页码 529-535出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20120499
关键词
enzyme kinetics; in vitro mutagenesis; mechanism of isoform selectivity; phosphoinositide 3-kinase (PI3K); small molecule inhibitor
资金
- National Health and Medical Research Council, Australia [5459431]
- National Cancer Institute, U.S.A. [R01]
The binding mechanism of a new class of lipid-competitive, ATP non-competitive, p110 alpha isoform-selective PI3K (phosphoinositide 3-kinase) inhibitors has been elucidated. Using the novel technique of isoform reciprocal mutagenesis of non-conserved amino acids in the p110 alpha and p110 beta isoforms, we have identified three unique binding mechanisms for the p110 alpha-selective inhibitors PIK-75, A-66S and J-32. Each of the inhibitor's p110 alpha-isoform-selective binding was found to be due to interactions with different amino acids within p110. The PIK-75 interaction bound the non-conserved region 2 amino acid p110 alpha Ser(773), A-66S bound the region 1 non-conserved amino acid p110 alpha Gln(859), and J-32 binding had an indirect interaction with Lys(776) and Ile(771). The isoform reciprocal mutagenesis technique is shown to be an important analytical tool for the rational design of isoform-selective inhibitors.
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