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Directed Evolution Mimics Allosteric Activation by Stepwise Tuning of the Conformational Ensemble

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    Directed Evolution Mimics Allosteric Activation by Stepwise Tuning of the Conformational Ensemble
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    • Andrew R. Buller*
      Andrew R. Buller
      Department of Chemistry, University of Wisconsin—Madison, 1101 University Avenue, Madison, Wisconsin 53706, United States
      Division of Chemistry and Chemical Engineering, California Institute of Technology, 210-41, 1200 East California Boulevard, Pasadena, California 91125, United States
      *[email protected]
      More by Andrew R. Buller
      Orcidhttp://orcid.org/0000-0002-9635-4844
    • Paul van Roye
      Paul van Roye
      Division of Chemistry and Chemical Engineering, California Institute of Technology, 210-41, 1200 East California Boulevard, Pasadena, California 91125, United States
      More by Paul van Roye
    • Jackson K. B. Cahn
      Jackson K. B. Cahn
      Institute of Microbiology, Eidgenössische Technische Hochschule (ETH) Zürich, Vladimir-Prelog-Weg 4, Zurich 8093, Switzerland
      More by Jackson K. B. Cahn
    • Remkes A. Scheele
      Remkes A. Scheele
      Division of Chemistry and Chemical Engineering, California Institute of Technology, 210-41, 1200 East California Boulevard, Pasadena, California 91125, United States
      More by Remkes A. Scheele
    • Michael Herger
      Michael Herger
      Division of Chemistry and Chemical Engineering, California Institute of Technology, 210-41, 1200 East California Boulevard, Pasadena, California 91125, United States
      More by Michael Herger
    • Frances H. Arnold
      Frances H. Arnold
      Division of Chemistry and Chemical Engineering, California Institute of Technology, 210-41, 1200 East California Boulevard, Pasadena, California 91125, United States
      More by Frances H. Arnold
      Orcidhttp://orcid.org/0000-0002-4027-364X
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    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2018, 140, 23, 7256–7266
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    https://doi.org/10.1021/jacs.8b03490
    Published April 30, 2018
    Copyright © 2018 American Chemical Society
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    Abstract

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    Allosteric enzymes contain a wealth of catalytic diversity that remains distinctly underutilized for biocatalysis. Tryptophan synthase is a model allosteric system and a valuable enzyme for the synthesis of noncanonical amino acids (ncAA). Previously, we evolved the β-subunit from Pyrococcus furiosus, PfTrpB, for ncAA synthase activity in the absence of its native partner protein PfTrpA. However, the precise mechanism by which mutation activated TrpB to afford a stand-alone catalyst remained enigmatic. Here, we show that directed evolution caused a gradual change in the rate-limiting step of the catalytic cycle. Concomitantly, the steady-state distribution of the intermediates shifts to favor covalently bound Trp adducts, which have increased thermodynamic stability. The biochemical properties of these evolved, stand-alone TrpBs converge on those induced in the native system by allosteric activation. High-resolution crystal structures of the wild-type enzyme, an intermediate in the lineage, and the final variant, encompassing five distinct chemical states, show that activating mutations have only minor structural effects on their immediate environment. Instead, mutation stabilizes the large-scale motion of a subdomain to favor an otherwise transiently populated closed conformational state. This increase in stability enabled the first structural description of Trp covalently bound in a catalytically active TrpB, confirming key features of catalysis. These data combine to show that sophisticated models of allostery are not a prerequisite to recapitulating its complex effects via directed evolution, opening the way to engineering stand-alone versions of diverse allosteric enzymes.

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    Cite this: J. Am. Chem. Soc. 2018, 140, 23, 7256–7266
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    Published April 30, 2018
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