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Inferential NMR/X-ray-Based Structure Determination of a Dibenzo[a,d]cycloheptenone Inhibitor–p38α MAP Kinase Complex in Solution

Authors

  • Dr. Valerie S. Honndorf,

    1. Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen (Germany)
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    • These authors contributed equally.

  • Dr. Nicolas Coudevylle,

    1. Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen (Germany)
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    • These authors contributed equally.

  • Prof. Dr. Stefan Laufer,

    1. Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard-Karls-University, Tübingen (Germany)
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  • Dr. Stefan Becker,

    1. Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen (Germany)
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  • Prof. Dr. Christian Griesinger,

    Corresponding author
    1. Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen (Germany)
    • Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen (Germany)
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  • Dr. Michael Habeck

    Corresponding author
    1. Department of Protein Evolution, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen (Germany)
    • Department of Protein Evolution, Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tübingen (Germany)
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  • M.H. acknowledges funding from the German Science Foundation (DFG HA 5918/1-1). C.G. thanks the Max Planck Society and the DFG (GRK 1034). We thank Thilo Stehle and Johannes Romir for providing the crystal structure and X-ray data for the p38α–1 complex.

Abstract

original image

Complex problem: The crystal structure of p38α mitogen-activated protein kinase in complex with a dibenzo[a,d]cycloheptenone inhibitor was found to be incompatible with NMR data of the same complex in solution. By using inferential structure determination (ISD) with restraints from X-ray crystallography and NMR spectra, a structure that is compatible with both data sets and very close to the X-ray crystal structure was generated (see picture).

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