Journal
SCIENCE
Volume 332, Issue 6026, Pages 234-238Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1198542
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Funding
- National Institutes of Health (NIH) [GM75995, GM080209]
- Skaggs Institute of Chemical Biology
- NIH National Institute of General Medical Sciences (NIGMS) [U54 GM094586]
- Achievement Rewards for College Scientists Foundation
- National Cancer Institute [Y1-CO-1020]
- NIGMS [Y1-GM-1104]
- U.S. Department of Energy, Basic Energy Sciences, Office of Science [DE-AC02-06CH11357]
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Conformational dynamics play a key role in enzyme catalysis. Although protein motions have clear implications for ligand flux, a role for dynamics in the chemical step of enzyme catalysis has not been clearly established. We generated a mutant of Escherichia coli dihydrofolate reductase that abrogates millisecond-time-scale fluctuations in the enzyme active site without perturbing its structural and electrostatic preorganization. This dynamic knockout severely impairs hydride transfer. Thus, we have found a link between conformational fluctuations on the millisecond time scale and the chemical step of an enzymatic reaction, with broad implications for our understanding of enzyme mechanisms and for design of novel protein catalysts.
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