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Structural and dynamic insights into the energetics of activation loop rearrangement in FGFR1 kinase

Author

Listed:
  • Tobias Klein

    (Discovery Sciences, AstraZeneca R&D
    Present addresses: Bayer Healthcare, GP Grenzach Produktions GmbH, Postfach 1146, D-79629 Grenzach-Wyhlen, Germany)

  • Navratna Vajpai

    (Discovery Sciences, AstraZeneca R&D
    Present address: Biological E. Ltd, ICICI Knowledge Park, Shameerpet, Ranga Reddy District, Hyderabad, Telangana 500078, India)

  • Jonathan J. Phillips

    (MedImmune
    Present address: Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, UK)

  • Gareth Davies

    (Discovery Sciences, AstraZeneca R&D)

  • Geoffrey A. Holdgate

    (Discovery Sciences, AstraZeneca R&D)

  • Chris Phillips

    (Discovery Sciences, AstraZeneca R&D)

  • Julie A. Tucker

    (Discovery Sciences, AstraZeneca R&D
    Present address: Northern Institute for Cancer Research, Paul O’Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK)

  • Richard A. Norman

    (Discovery Sciences, AstraZeneca R&D)

  • Andrew D. Scott

    (Discovery Sciences, AstraZeneca R&D
    Present address: Molplex Ltd, BioHub at Alderley Park, Alderley Park, Macclesfield SK10 4TG, UK)

  • Daniel R. Higazi

    (MedImmune)

  • David Lowe

    (MedImmune)

  • Gary S. Thompson

    (Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds)

  • Alexander L. Breeze

    (Discovery Sciences, AstraZeneca R&D
    Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds
    Present address: Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK)

Abstract

Protein tyrosine kinases differ widely in their propensity to undergo rearrangements of the N-terminal Asp–Phe–Gly (DFG) motif of the activation loop, with some, including FGFR1 kinase, appearing refractory to this so-called ‘DFG flip’. Recent inhibitor-bound structures have unexpectedly revealed FGFR1 for the first time in a ‘DFG-out’ state. Here we use conformationally selective inhibitors as chemical probes for interrogation of the structural and dynamic features that appear to govern the DFG flip in FGFR1. Our detailed structural and biophysical insights identify contributions from altered dynamics in distal elements, including the αH helix, towards the outstanding stability of the DFG-out complex with the inhibitor ponatinib. We conclude that the αC-β4 loop and ‘molecular brake’ regions together impose a high energy barrier for this conformational rearrangement, and that this may have significance for maintaining autoinhibition in the non-phosphorylated basal state of FGFR1.

Suggested Citation

  • Tobias Klein & Navratna Vajpai & Jonathan J. Phillips & Gareth Davies & Geoffrey A. Holdgate & Chris Phillips & Julie A. Tucker & Richard A. Norman & Andrew D. Scott & Daniel R. Higazi & David Lowe & , 2015. "Structural and dynamic insights into the energetics of activation loop rearrangement in FGFR1 kinase," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8877
    DOI: 10.1038/ncomms8877
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    Cited by:

    1. Han Li & Ruotian Zhang & Yaosen Min & Dacheng Ma & Dan Zhao & Jianyang Zeng, 2023. "A knowledge-guided pre-training framework for improving molecular representation learning," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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