Comparative surface geometry of the protein kinase family

Authors

  • Elaine E. Thompson,

    1. Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093
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  • Alexandr P. Kornev,

    1. Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030
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  • Natarajan Kannan,

    1. Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602-7229
    2. Institute of Bioinformatics, University of Georgia, Athens, GA 30602-7229
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  • Choel Kim,

    1. Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030
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  • Lynn F. Ten Eyck,

    Corresponding author
    1. Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093
    2. San Diego Supercomputer Center, University of California at San Diego, La Jolla, CA 92093
    • San Diego Supercomputer Center, University of California at San Diego, La Jolla, CA 92093
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  • Susan S. Taylor

    1. Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093
    2. Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030
    3. Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093
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  • The clustering analysis for this article was generated using SAS software, Version 9.1 of the SAS System for Windows. Copyright © 2002-2003 SAS Institute Inc. SAS and all other SAS Institute Inc. product or service names are registered trademarks or trademarks of SAS Institute Inc., Cary, NC, USA.

Abstract

Identifying conserved pockets on the surfaces of a family of proteins can provide insight into conserved geometric features and sites of protein–protein interaction. Here we describe mapping and comparison of the surfaces of aligned crystallographic structures, using the protein kinase family as a model. Pockets are rapidly computed using two computer programs, FADE and Crevasse. FADE uses gradients of atomic density to locate grooves and pockets on the molecular surface. Crevasse, a new piece of software, splits the FADE output into distinct pockets. The computation was run on 10 kinase catalytic cores aligned on the αF-helix, and the resulting pockets spatially clustered. The active site cleft appears as a large, contiguous site that can be subdivided into nucleotide and substrate docking sites. Substrate specificity determinants in the active site cleft between serine/threonine and tyrosine kinases are visible and distinct. The active site clefts cluster tightly, showing a conserved spatial relationship between the active site and αF-helix in the C-lobe. When the αC-helix is examined, there are multiple mechanisms for anchoring the helix using spatially conserved docking sites. A novel site at the top of the N-lobe is present in all the kinases, and there is a large conserved pocket over the hinge and the αC-β4 loop. Other pockets on the kinase core are strongly conserved but have not yet been mapped to a protein–protein interaction. Sites identified by this algorithm have revealed structural and spatially conserved features of the kinase family and potential conserved intermolecular and intramolecular binding sites.

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