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Comparative surface geometry of the protein kinase family†

  1. Elaine E. Thompson1,
  2. Alexandr P. Kornev2,
  3. Natarajan Kannan3,4,
  4. Choel Kim2,
  5. Lynn F. Ten Eyck1,5,*,
  6. Susan S. Taylor1,2,6

Article first published online: 16 JUL 2009

DOI: 10.1002/pro.209

Issue

Protein Science

Protein Science

Volume 18, Issue 10, pages 2016–2026, October 2009

Additional Information

How to Cite

Thompson, E. E., Kornev, A. P., Kannan, N., Kim, C., Ten Eyck, L. F. and Taylor, S. S. (2009), Comparative surface geometry of the protein kinase family. Protein Science, 18: 2016–2026. doi: 10.1002/pro.209

Author Information

  1. 1

    Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093

  2. 2

    Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030

  3. 3

    Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602-7229

  4. 4

    Institute of Bioinformatics, University of Georgia, Athens, GA 30602-7229

  5. 5

    San Diego Supercomputer Center, University of California at San Diego, La Jolla, CA 92093

  6. 6

    Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093

*San Diego Supercomputer Center, University of California at San Diego, La Jolla, CA 92093

  1. †

    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.

Publication History

  1. Issue published online: 23 SEP 2009
  2. Article first published online: 16 JUL 2009
  3. Accepted manuscript online: 16 JUL 2009 12:00AM EST
  4. Manuscript Accepted: 24 JUN 2009
  5. Manuscript Revised: 15 JUN 2009
  6. Manuscript Received: 23 MAR 2009

Funded by

  • National Institute of Health. Grant Number: GM19301
  • National Institute of General Medical Sciences. Grant Number: R01GM070996
  • UCSD Bioinformatics Graduate Program

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Keywords:

  • kinase;
  • protein kinase A;
  • pockets;
  • protein surface

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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