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Science 15 September 2006:
Vol. 313. no. 5793, pp. 1638 - 1642
DOI: 10.1126/science.1130258
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Reports

The Dynamic Energy Landscape of Dihydrofolate Reductase Catalysis

David D. Boehr, Dan McElheny,* H. Jane Dyson, Peter E. Wright{dagger}

We used nuclear magnetic resonance relaxation dispersion to characterize higher energy conformational substates of Escherichia coli dihydrofolate reductase. Each intermediate in the catalytic cycle samples low-lying excited states whose conformations resemble the ground-state structures of preceding and following intermediates. Substrate and cofactor exchange occurs through these excited substates. The maximum hydride transfer and steady-state turnover rates are governed by the dynamics of transitions between ground and excited states of the intermediates. Thus, the modulation of the energy landscape by the bound ligands funnels the enzyme through its reaction cycle along a preferred kinetic path.

Department of Molecular Biology and Skaggs Institute for Chemical Biology, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

* Present address: Division of Biological Sciences, University of Chicago, Chicago, IL 60637, USA.

{dagger} To whom correspondence should be addressed. E-mail: wright{at}scripps.edu

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Science. ISSN 0036-8075 (print), 1095-9203 (online)