The Dynamic Energy Landscape of Dihydrofolate Reductase Catalysis

Author:

Boehr David D.1,McElheny Dan1,Dyson H. Jane1,Wright Peter E.1

Affiliation:

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

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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