Dissecting isoform selectivity of P13K inhibitors: the role of non-conserved residues in the catalytic pocket

Frazzetto, Mark, Suphioglu, Cenk, Zhu, Jiuxiang, Schmidt-Kittler, Oleg, Jennings, Ian, Cranmer, Susan, Jackson, Shaun, Kinzler, Kenneth, Vogelstein, Bert and Thompson, Philip 2008, Dissecting isoform selectivity of P13K inhibitors: the role of non-conserved residues in the catalytic pocket, Biochemical journal, vol. 414, no. 3, pp. 383-390, doi: 10.1042/BJ20080512.

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Title Dissecting isoform selectivity of P13K inhibitors: the role of non-conserved residues in the catalytic pocket
Author(s) Frazzetto, Mark
Suphioglu, CenkORCID iD for Suphioglu, Cenk orcid.org/0000-0003-0101-0668
Zhu, Jiuxiang
Schmidt-Kittler, Oleg
Jennings, Ian
Cranmer, Susan
Jackson, Shaun
Kinzler, Kenneth
Vogelstein, Bert
Thompson, Philip
Journal name Biochemical journal
Volume number 414
Issue number 3
Start page 383
End page 390
Total pages 8
Publisher Portland Press Ltd
Place of publication London, England
Publication date 2008
ISSN 0264-6021
Keyword(s) ATP-binding pocket
phosphoinositide 3-kinase (PI3K)
site-directed mutagenesis
small-molecule inhibitor
Summary The last few years have seen the identification of numerous small molecules that selectively inhibit specific class I isoforms of PI3K (phosphoinositide 3-kinase), yet little has been revealed about the molecular basis for the observed selectivities. Using site-directed mutagenesis, we have investigated one of the areas postulated as being critical to the observed selectivity. The residues Thr886 and Lys890 of the PI3Kγ isoform project towards the ATP-binding pocket at the entrance to the catalytic site, but are not conserved. We have made reciprocal mutations between those residues in the β isoform (Glu858 and Asp862) and those in the α isoform (His855 and Gln859) and evaluated the potency of a range of reported PI3K inhibitors. The results show that the potencies of β-selective inhibitors TGX221 and TGX286 are unaffected by this change. In contrast, close analogues of these compounds, particularly the α-isoform-selective compound (III), are markedly influenced by the point mutations. The collected data suggests two distinct binding poses for these inhibitor classes, one of which is associated with potent PI3Kβ activity and is not associated with the mutated residues, and a second that, in accord with earlier hypotheses, does involve this pair of non-conserved amino acids at the catalytic site entrance and contributes to the α-isoform-selectivity of the compounds studied.
Language eng
DOI 10.1042/BJ20080512
Field of Research 110106 Medical Biochemistry: Proteins and Peptides (incl Medical Proteomics)
HERDC Research category C1 Refereed article in a scholarly journal
HERDC collection year 2008
Copyright notice ©2008, The Authors
Persistent URL http://hdl.handle.net/10536/DRO/DU:30017432

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