Rescue of conformational dynamics in enzyme catalysis by directed evolution

Otten, Renee; Liu, Lin; Kenner, Lillian R.; Clarkson, Michael W.; Mavor, David; Tawfik, Dan S.; Kern, Dorothee; Fraser, James S.

doi:10.1038/s41467-018-03562-9

Title: Rescue of conformational dynamics in enzyme catalysis by directed evolution

Journal Article · Tue Apr 03 00:00:00 EDT 2018 · Nature Communications

DOI:https://doi.org/10.1038/s41467-018-03562-9· OSTI ID:1499927

^[1]; Liu, Lin ^[2]; Kenner, Lillian R. ^[2]; Clarkson, Michael W. ^[1]; Mavor, David ^[2]; Tawfik, Dan S. ^[3]; Kern, Dorothee ^[1];

^[2]

Brandeis Univ., Waltham, MA (United States)
Univ. of California, San Francisco, CA (United States)
Weizmann Inst. of Science, Rehovot (Israel)

Rational design and directed evolution have proved to be successful approaches to increase catalytic efficiencies of both natural and artificial enzymes. Protein dynamics is recognized as important, but due to the inherent flexibility of biological macromolecules it is often difficult to distinguish which conformational changes are directly related to function. Here, we use directed evolution on an impaired mutant of the proline isomerase CypA and identify two second-shell mutations that partially restore its catalytic activity. We show both kinetically, using NMR spectroscopy, and structurally, by room-temperature X-ray crystallography, how local perturbations propagate through a large allosteric network to facilitate conformational dynamics. The increased catalysis selected for in the evolutionary screen is correlated with an accelerated interconversion between the two catalytically essential conformational sub-states, which are both captured in the high-resolution X-ray ensembles. Our data provide a glimpse of an evolutionary trajectory and show how subtle changes can fine-tune enzyme function.

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Research Organization:: Brandeis Univ., Waltham, MA (United States); Univ. of California, San Francisco, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: FG02-05ER15699; AC02-05CH11231

OSTI ID:: 1499927

Journal Information:: Nature Communications, Vol. 9, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 67 works

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