Design of drug-resistant alleles of type-III phosphatidylinositol 4-kinases using mutagenesis and molecular modeling

Biochemistry
Andras BallaT Balla

Abstract

Molecular modeling and site directed mutagenesis were used to analyze the structural features determining the unique inhibitor sensitivities of type-III phosphatidylinositol 4-kinase enzymes (PI4Ks). Mutation of a highly conserved Tyr residue that provides the bottom of the hydrophobic pocket for ATP yielded a PI4KIIIbeta enzyme that showed greatly reduced wortmannin sensitivity and was catalytically still active. Similar substitutions were not tolerated in the type-IIIalpha enzyme rendering it catalytically inactive. Two conserved Cys residues located in the active site of PI4KIIIalpha were found responsible for the high sensitivity of this enzyme to the oxidizing agent, phenylarsine oxide. Mutation of one of these Cys residues reduced the phenylarsine oxide sensitivity of the enzyme to the same level observed with the PI4KIIIbeta protein. In search of inhibitors that would discriminate between the closely related PI4KIIIalpha and -IIIbeta enzymes, the PI3Kgamma inhibitor, PIK93, was found to inhibit PI4KIIIbeta with significantly greater potency than PI4KIIIalpha. These studies should aid development of subtype-specific inhibitors of type-III PI4Ks and help to better understand the significance of localized PtdIns4P productio...Continue Reading

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Citations

Aug 4, 2011·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Eleonora ZakharianTibor Rohacs
Apr 9, 2014·The Journal of Cell Biology·Gerald R V HammondTamas Balla
Jul 18, 2015·Experimental Cell Research·Evzen Boura, Radim Nencka
Apr 5, 2016·Proceedings of the National Academy of Sciences of the United States of America·Mira SohnTamas Balla
Aug 18, 2012·Plant Signaling & Behavior·Elise DelageJuliette Puyaubert
Jun 28, 2011·Analytical Biochemistry·Andrew W TaiTamas Balla
Oct 2, 2019·Physical Chemistry Chemical Physics : PCCP·Shuaizhen TianTong Zhu
Dec 13, 2017·Proceedings of the National Academy of Sciences of the United States of America·Joshua A LeesKarin M Reinisch
May 10, 2021·Bioorganic & Medicinal Chemistry·Alex G Batrouni, Jeremy M Baskin
May 22, 2021·Neuroscience Bulletin·Linan ZhengWenan Wang

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