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Publication Abstract from PubMed

MtsZ is a molybdenum-containing methionine sulfoxide (MetSO) 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 MetSO 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 the 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 DMSO 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.

Active site architecture reveals coordination sphere flexibility and specificity determinants in a group of closely related molybdoenzymes.,Struwe MA, Kalimuthu P, Luo Z, Zhong Q, Ellis D, Yang J, Kc K, Harmer JR, Kirk ML, McEwan AG, Clement B, Bernhardt PV, Kobe B, Kappler U J Biol Chem. 2021 Apr 19:100672. doi: 10.1016/j.jbc.2021.100672. PMID:33887324^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.