Diverse dynamics features of novel protein kinase C (PKC) isozymes determine the selectivity of a fluorinated balanol analogue for PKCε
| العنوان: | Diverse dynamics features of novel protein kinase C (PKC) isozymes determine the selectivity of a fluorinated balanol analogue for PKCε |
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| المؤلفون: | Varun Khanna, Fei Liu, Ari Hardianto, Shoba Ranganathan |
| المصدر: | BMC Bioinformatics, Vol 19, Iss S13, Pp 187-197 (2019) BMC Bioinformatics |
| بيانات النشر: | Springer Science and Business Media LLC, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Halogenation, Protein Conformation, Ribose, Static Electricity, Fluorinated balanol analogue selectivity, Protein Kinase C-epsilon, Molecular Dynamics Simulation, lcsh:Computer applications to medicine. Medical informatics, 01 natural sciences, Biochemistry, Isozyme, Substrate Specificity, Balanol, 03 medical and health sciences, chemistry.chemical_compound, Adenosine Triphosphate, Structural Biology, 0103 physical sciences, Hydroxybenzoates, Cluster Analysis, Humans, Phosphorylation, Novel PKC isozymes, Protein kinase A, lcsh:QH301-705.5, Molecular Biology, Protein kinase C, chemistry.chemical_classification, PKCε, 010304 chemical physics, Molecular dynamics simulations, Chemistry, Kinase, Research, Applied Mathematics, Rational design, Azepines, Computer Science Applications, Isoenzymes, 030104 developmental biology, Enzyme, lcsh:Biology (General), Unique dynamics feature, lcsh:R858-859.7, Sequence Alignment |
| الوصف: | Background (−)-Balanol is an ATP-mimicking inhibitor that non-selectively targets protein kinase C (PKC) isozymes and cAMP-dependent protein kinase (PKA). While PKA constantly shows tumor promoting activities, PKC isozymes can ambiguously be tumor promoters or suppressors. In particular, PKCε is frequently implicated in tumorigenesis and a potential target for anticancer drugs. We recently reported that the C5(S)-fluorinated balanol analogue (balanoid 1c) had improved binding affinity and selectivity for PKCε but not to the other novel PKC isozymes, which share a highly similar ATP site. The underlying basis for this fluorine-based selectivity is not entirely comprehended and needs to be investigated further for the development of ATP mimic inhibitors specific for PKCε. Results Using molecular dynamics (MD) simulations assisted by homology modelling and sequence analysis, we have studied the fluorine-based selectivity in the highly similar ATP sites of novel PKC (nPKC) isozymes. The study suggests that every nPKC isozyme has different dynamics behaviour in both apo and 1c-bound forms. Interestingly, the apo form of PKCε, where 1c binds strongly, shows the highest degree of flexibility which dramatically decreases after binding 1c. Conclusions For the first time to the best of our knowledge, we found that the origin of 1c selectivity for PKCε comes from the unique dynamics feature of each PKC isozyme. Fluorine conformational control in 1c can synergize with and lock down the dynamics of PKCε, which optimize binding interactions with the ATP site residues of the enzyme, particularly the invariant Lys437. This finding has implications for further rational design of balanol-based PKCε inhibitors for cancer drug development. Electronic supplementary material The online version of this article (10.1186/s12859-018-2373-1) contains supplementary material, which is available to authorized users. |
| تدمد: | 1471-2105 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cc933e2445c7c68f781adf366220155b https://doi.org/10.1186/s12859-018-2373-1 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....cc933e2445c7c68f781adf366220155b |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 14712105 |
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