Hidden alternative structures of proline isomerase essential for catalysis

James S. Fraser, Michael W. Clarkson, Sheena C. Degnan, Renske Erion, Dorothee Kern () and Tom Alber ()
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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

Nature, 2009, vol. 462, issue 7273, 669-673

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.

Date: 2009
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DOI: 10.1038/nature08615

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