期刊
NATURE CHEMISTRY
卷 8, 期 5, 页码 419-425出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEM.2474
关键词
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资金
- Gordon and Betty Moore Foundation [GBMF2809]
- Ruth L. Kirschstein National Research Service Award postdoctoral fellowship from the National Institutes of Health (NIH) [5F32GM106618]
- Lawrence Scholars Program
- NIH Simbios Program [U54 GM072970]
- Center for Molecular Analysis and Design (Stanford)
- Resnick Sustainability Institute (Caltech)
- Beckman Institute
- Sanofi-Aventis Bioengineering Research Program (Caltech)
- National Science Foundation [OCI-0725070, ACI-1238993]
- state of Illinois
The dynamic motions of protein structural elements, particularly flexible loops, are intimately linked with diverse aspects of enzyme catalysis. Engineering of these loop regions can alter protein stability, substrate binding and even dramatically impact enzyme function. When these flexible regions are unresolvable structurally, computational reconstruction in combination with large-scale molecular dynamics simulations can be used to guide the engineering strategy. Here we present a collaborative approach that consists of both experiment and computation and led to the discovery of a single mutation in the F/G loop of the nitrating cytochrome P450 TxtE that simultaneously controls loop dynamics and completely shifts the enzyme's regioselectivity from the C4 to the C5 position of L-tryptophan. Furthermore, we find that this loop mutation is naturally present in a subset of homologous nitrating P450s and confirm that these uncharacterized enzymes exclusively produce 5-nitro-L-tryptophan, a previously unknown biosynthetic intermediate.
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