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Evaluation of cancer dependence and druggability of PRP4 kinase using cellular, biochemical, and structural approaches.

ABSTRACT: PRP4 kinase is known for its roles in regulating pre-mRNA splicing and beyond. Therefore, a wider spectrum of PRP4 kinase substrates could be expected. The role of PRP4 kinase in cancer is also yet to be fully elucidated. Attaining specific and potent PRP4 inhibitors would greatly facilitate the study of PRP4 biological function and its validation as a credible cancer target. In this report, we verified the requirement of enzymatic activity of PRP4 in regulating cancer cell growth and identified an array of potential novel substrates through orthogonal proteomics approaches. The ensuing effort in structural biology unveiled for the first time unique features of PRP4 kinase domain and its potential mode of interaction with a low molecular weight inhibitor. These results provide new and important information for further exploration of PRP4 kinase function in cancer.

SUBMITTER: Gao Q

PROVIDER: S-EPMC3798481 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Evaluation of cancer dependence and druggability of PRP4 kinase using cellular, biochemical, and structural approaches.

Gao Qiang Q Mechin Ingrid I Kothari Nayantara N Guo Zhuyan Z Deng Gejing G Haas Kimberly K McManus Jessica J Hoffmann Dietmar D Wang Anlai A Wiederschain Dmitri D Rocnik Jennifer J Czechtizky Werngard W Chen Xin X McLean Larry L Arlt Heike H Harper David D Liu Feng F Majid Tahir T Patel Vinod V Lengauer Christoph C Garcia-Echeverria Carlos C Zhang Bailin B Cheng Hong H Dorsch Marion M Huang Shih-Min A SA

The Journal of biological chemistry 20130903 42

PRP4 kinase is known for its roles in regulating pre-mRNA splicing and beyond. Therefore, a wider spectrum of PRP4 kinase substrates could be expected. The role of PRP4 kinase in cancer is also yet to be fully elucidated. Attaining specific and potent PRP4 inhibitors would greatly facilitate the study of PRP4 biological function and its validation as a credible cancer target. In this report, we verified the requirement of enzymatic activity of PRP4 in regulating cancer cell growth and identified ...[more]

PMID: 24003220

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Project description:IntroductionThe structural and dynamic determinants that confer highly selective RET kinase inhibition are poorly understood.ObjectivesTo explore the druggability landscape of the RET active site in order to uncover structural and dynamic vulnerabilities that can be therapeutically exploited.MethodsWe apply an integrated structural, computational and biochemical approach in order to explore the druggability landscape of the RET active site.ResultsWe demonstrate that the that the druggability landscape of the RET active site is determined by the conformational setting of the ATP-binding (P-) loop and its coordination with the αC helix. Open and intermediate P-loop structures display additional druggable vulnerabilities within the active site that were not exploited by first generation RET inhibitors. We identify a cryptic pocket adjacent to the catalytic lysine formed by K758, L760, E768 and L772, that we name the post-lysine pocket, with higher druggability potential than the adenine-binding site and with important implications in the regulation of the phospho-tyrosine kinase activity. Crystal structure and simulation data show that the binding mode of highly-selective RET kinase inhibitors LOXO-292 and BLU-667 is controlled by a synchronous open P-loop and αC-in configuration that allows accessibility to the post-lysine pocket. Molecular dynamics simulations show that these inhibitors efficiently occupy the post-lysine pocket with high stability through the simulation time-scale (300 ns), with both inhibitors forming hydrophobic contacts further stabilized by pi-cation interactions with the catalytic K758. Engineered mutants targeting the post-lysine pocket impact on inhibitor binding and sensitivity, as well as RET tyrosine kinase activity.ConclusionsThe identification of the post-lysine pocket as a new druggable vulnerability in the RET kinase and its exploitation by second generation RET inhibitors have important implications for future drug design and the development of personalized therapies for patients with RET-driven cancers.

Dataset Information

Evaluation of cancer dependence and druggability of PRP4 kinase using cellular, biochemical, and structural approaches.

Publications

Evaluation of cancer dependence and druggability of PRP4 kinase using cellular, biochemical, and structural approaches.

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