Active site architecture reveals coordination sphere flexibility and specificity determinants in a group of closely related molybdoenzymes.

Autor:	Struwe MA; Australian Infectious Disease Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Qld, Australia; Pharmazeutisches Institut, Christian-Albrechts-Universität Kiel, Kiel, Germany., Kalimuthu P; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Qld, Australia., Luo Z; Australian Infectious Disease Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Qld, Australia; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld, Australia., Zhong Q; Australian Infectious Disease Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Qld, Australia., Ellis D; Australian Infectious Disease Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Qld, Australia., Yang J; Department of Chemistry and Chemical Biology, The University of New Mexico, Albuquerque, New Mexico, USA., Khadanand KC; Department of Chemistry and Chemical Biology, The University of New Mexico, Albuquerque, New Mexico, USA., Harmer JR; Centre for Advanced Imaging, The University of Queensland, Brisbane, Qld, Australia., Kirk ML; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld, Australia., McEwan AG; Australian Infectious Disease Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Qld, Australia., Clement B; Pharmazeutisches Institut, Christian-Albrechts-Universität Kiel, Kiel, Germany., Bernhardt PV; School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Qld, Australia., Kobe B; Australian Infectious Disease Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Qld, Australia; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld, Australia., Kappler U; Australian Infectious Disease Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Qld, Australia. Electronic address: u.kappler@uq.edu.au.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2021 Jan-Jun; Vol. 296, pp. 100672. Date of Electronic Publication: 2021 Apr 20.
DOI:	10.1016/j.jbc.2021.100672
Abstrakt:	MtsZ is a molybdenum-containing methionine sulfoxide reductase that supports virulence in the human respiratory pathogen Haemophilus influenzae (Hi). HiMtsZ belongs to a group of structurally and spectroscopically uncharacterized S-/N-oxide reductases, all of which are found in bacterial pathogens. Here, we have solved the crystal structure of HiMtsZ, which reveals that the HiMtsZ substrate-binding site encompasses a previously unrecognized part that accommodates the methionine sulfoxide side chain via interaction with His182 and Arg166. Charge and amino acid composition of this side chain-binding region vary and, as indicated by electrochemical, kinetic, and docking studies, could explain the diverse substrate specificity seen in closely related enzymes of this type. The HiMtsZ Mo active site has an underlying structural flexibility, where dissociation of the central Ser187 ligand affected catalysis at low pH. Unexpectedly, the two main HiMtsZ electron paramagnetic resonance (EPR) species resembled not only a related dimethyl sulfoxide reductase but also a structurally unrelated nitrate reductase that possesses an Asp-Mo ligand. This suggests that contrary to current views, the geometry of the Mo center and its primary ligands, rather than the specific amino acid environment, is the main determinant of the EPR properties of mononuclear Mo enzymes. The flexibility in the electronic structure of the Mo centers is also apparent in two of three HiMtsZ EPR-active Mo(V) species being catalytically incompetent off-pathway forms that could not be fully oxidized. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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