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Comput Math Methods Med. 2014;2014:653487. doi: 10.1155/2014/653487. Epub 2014 Apr 8.

Structure-functional prediction and analysis of cancer mutation effects in protein kinases.

Author information

1
Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas, 2010 Becker Drive, Lawrence, KS 66047, USA ; Department of Biotechnology, Institute of Life Sciences, Bhubaneswar, India.
2
School of Computational Sciences and Crean School of Health and Life Sciences, Schmid College of Science and Technology, Chapman University, One University Drive, Orange, CA 92866, USA ; Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.

Abstract

A central goal of cancer research is to discover and characterize the functional effects of mutated genes that contribute to tumorigenesis. In this study, we provide a detailed structural classification and analysis of functional dynamics for members of protein kinase families that are known to harbor cancer mutations. We also present a systematic computational analysis that combines sequence and structure-based prediction models to characterize the effect of cancer mutations in protein kinases. We focus on the differential effects of activating point mutations that increase protein kinase activity and kinase-inactivating mutations that decrease activity. Mapping of cancer mutations onto the conformational mobility profiles of known crystal structures demonstrated that activating mutations could reduce a steric barrier for the movement from the basal "low" activity state to the "active" state. According to our analysis, the mechanism of activating mutations reflects a combined effect of partial destabilization of the kinase in its inactive state and a concomitant stabilization of its active-like form, which is likely to drive tumorigenesis at some level. Ultimately, the analysis of the evolutionary and structural features of the major cancer-causing mutational hotspot in kinases can also aid in the correlation of kinase mutation effects with clinical outcomes.

PMID:
24817905
PMCID:
PMC4000980
DOI:
10.1155/2014/653487
[Indexed for MEDLINE]
Free PMC Article

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