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Hidden alternative structures of proline isomerase essential for catalysis

Author

Listed:
  • James S. Fraser

    (University of California, Berkeley, California 94720-3220, USA)

  • Michael W. Clarkson

    (Howard Hughes Medical Institute, Brandeis University, Waltham, Massachusetts 02454, USA)

  • Sheena C. Degnan

    (University of California, Berkeley, California 94720-3220, USA)

  • Renske Erion

    (University of California, Berkeley, California 94720-3220, USA)

  • Dorothee Kern

    (Howard Hughes Medical Institute, Brandeis University, Waltham, Massachusetts 02454, USA)

  • Tom Alber

    (University of California, Berkeley, California 94720-3220, USA)

Abstract

Altered states: in search of 'hidden' protein structures X-ray crystallography and NMR spectroscopy are two powerful tools used by structural biologists to determine the three-dimensional structures and characterize the dynamic properties of proteins. In this paper, the authors used both of these methods to identify and characterize a 'hidden' high-energy substate of human cyclophilin A, a proline isomerase. This was made possible by engineering a modified form of the enzyme incorporating a mutation at a distance from the active site that could stabilize this previously hidden conformation by inverting the equilibrium between the various substates and reducing the conformational interconversion rates and the catalytic rate. This approach should be broadly applicable to many other proteins and could lead to the reinterpretation of crystal structures determined previously.

Suggested Citation

  • James S. Fraser & Michael W. Clarkson & Sheena C. Degnan & Renske Erion & Dorothee Kern & Tom Alber, 2009. "Hidden alternative structures of proline isomerase essential for catalysis," Nature, Nature, vol. 462(7273), pages 669-673, December.
    • Handle: RePEc:nat:nature:v:462:y:2009:i:7273:d:10.1038_nature08615
    DOI: 10.1038/nature08615
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    Cited by:

    1. Tiberiu Teşileanu & Lucy J Colwell & Stanislas Leibler, 2015. "Protein Sectors: Statistical Coupling Analysis versus Conservation," PLOS Computational Biology, Public Library of Science, vol. 11(2), pages 1-20, February.
    2. Antony D. St-Jacques & Joshua M. Rodriguez & Matthew G. Eason & Scott M. Foster & Safwat T. Khan & Adam M. Damry & Natalie K. Goto & Michael C. Thompson & Roberto A. Chica, 2023. "Computational remodeling of an enzyme conformational landscape for altered substrate selectivity," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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