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A Gaussian network model study suggests that structural fluctuations are higher for inactive states than active states of protein kinases

Kalaivani, Raju and Srinivasan, Narayanaswamy (2015) A Gaussian network model study suggests that structural fluctuations are higher for inactive states than active states of protein kinases. In: MOLECULAR BIOSYSTEMS, 11 (4). pp. 1079-1095.

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Official URL: http://dx.doi.org/10.1039/c4mb00675e

Abstract

We performed Gaussian network model based normal mode analysis of 3-dimensional structures of multiple active and inactive forms of protein kinases. In 14 different kinases, a more number of residues (1095) show higher structural fluctuations in inactive states than those in active states (525), suggesting that, in general, mobility of inactive states is higher than active states. This statistically significant difference is consistent with higher crystallographic B-factors and conformational energies for inactive than active states, suggesting lower stability of inactive forms. Only a small number of inactive conformations with the DFG motif in the ``in'' state were found to have fluctuation magnitudes comparable to the active conformation. Therefore our study reports for the first time, intrinsic higher structural fluctuation for almost all inactive conformations compared to the active forms. Regions with higher fluctuations in the inactive states are often localized to the aC-helix, aG-helix and activation loop which are involved in the regulation and/or in structural transitions between active and inactive states. Further analysis of 476 kinase structures involved in interactions with another domain/protein showed that many of the regions with higher inactive-state fluctuation correspond to contact interfaces. We also performed extensive GNM analysis of (i) insulin receptor kinase bound to another protein and (ii) holo and apo forms of active and inactive conformations followed by multi-factor analysis of variance. We conclude that binding of small molecules or other domains/proteins reduce the extent of fluctuation irrespective of active or inactive forms. Finally, we show that the perceived fluctuations serve as a useful input to predict the functional state of a kinase.

Item Type: Journal Article
Additional Information: Copy right for this article belongs to the ROYAL SOC CHEMISTRY, THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND
Keywords: ACTIVATION LOOP PHOSPHORYLATION; ALPHA-C HELIX; BIOMOLECULAR COMPLEXES; VIBRATIONAL DYNAMICS; SINGLE-PARAMETER; FOLDED PROTEINS; DOMAIN MOTIONS; FLEXIBILITY; BINDING; CONFORMATION
Department/Centre: Division of Biological Sciences > Microbiology & Cell Biology
Depositing User: Id for Latest eprints
Date Deposited: 24 Apr 2015 06:13
Last Modified: 24 Apr 2015 06:13
URI: http://eprints.iisc.ac.in/id/eprint/51400

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