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Characterization of Conformational Patterns in Active and Inactive Forms of Kinases Using Protein Blocks Approach.

Abstract : The three-dimensional structure being critical for the function of a protein is usually conserved during evolution. It holds a wealth of information which can be harnessed to understand various aspects of proteins including sequence- structure function and evolutionary relationships. The understanding of these complex relationships is facilitated by a simplistic one-dimensional representation of the tertiary structure like a string of letters. The advantage is an easier visualization without losing much of the vital information due to dimension reduction. Using various methodologies, local structural patterns that can be combined to generate the desired backbone conformation, have been identified that use atomic coordinates characterising three-dimensional structures of proteins. Protein Blocks (PBs) is a set of 16 such local structural descriptors, denoted by letters a .. p that has been derived using unsupervised machine learning algorithms and can approximate the three dimensional space of proteins. Each letter corresponds to a entapeptide with distinct values of 8 dihedral angles (phi, psi). We demonstrate the use of PBs to characterize structural variations in enzymes using kinases as the case study. A protein kinase undergoes structural alterations as it switches to its active conformation from its inactive form. Crystal structures of several protein kinases are available in different enzymatic states. Firstly, we have applied PBs approach in distinguishing between conformation changes and rigid body displacements between the structures of active and inactive forms of a kinase. Secondly, we have performed a comparison of conformational patterns of active forms of a kinase with the active and inactive forms of a closely related kinase. Thirdly, we have studied the structural differences in the active states of homologous kinases. Such studies might help in understanding the structural differences among these enzymes at a different level as well as guide in making drug targets for a specific kinase. The first section gives a brief introduction on PBs and protein kinases followed by the analyses on conformational plasticity in kinases using Protein Blocks.
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https://www.hal.inserm.fr/inserm-00557296
Contributor : Alexandre G. de Brevern <>
Submitted on : Tuesday, January 18, 2011 - 7:12:10 PM
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Garima Agarwal, Dhurvas Chandrasekaran Dinesh, Narayanaswamy Srinivasan, Alexandre de Brevern. Characterization of Conformational Patterns in Active and Inactive Forms of Kinases Using Protein Blocks Approach.. Ujjwal Maulik, Sanghamitra Bandyopadhyay, Jason T. L. Wang. Computational Intelligence and Pattern Analysis in Biological Informatics, Wiley, pp.169-188, 2010, ⟨10.1002/9780470872352.ch8⟩. ⟨inserm-00557296⟩

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