The Dynamic Energy Landscape of Dihydrofolate Reductase Catalysis

American Association for the Advancement of Science (AAAS) - Tập 313 Số 5793 - Trang 1638-1642 - 2006
David D. Boehr1, Dan McElheny1, H. Jane Dyson1, Peter E. Wright1
1Department of Molecular Biology and Skaggs Institute for Chemical Biology, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

Tóm tắt

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.

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We thank J. Chung and G. Kroon for assistance with the NMR experiments L. Tennant for technical assistance and S. Benkovic for valuable discussions. This work was supported by NIH grants GM56879 and GM75995 and by the Skaggs Institute for Chemical Biology. D.D.B. was a recipient of a Canadian Institutes of Health Research postdoctoral fellowship. D.M. was supported by a postdoctoral fellowship from NIH.

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American Association for the Advancement of Science (AAAS)

Tập 313 Số 5793

1638-1642

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