期刊
PROTEIN SCIENCE
卷 24, 期 11, 页码 1777-1788出版社
WILEY
DOI: 10.1002/pro.2768
关键词
superoxide dismutase; conformational variation; MnSOD-3-azide complex; catalytic mechanism; product inhibition
资金
- University of Malta [PHBRP02]
- Dean's Research Award [MDSIN08-19, MEDIN08-01]
- US Department of Energy, Office of Science, Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences, and Biosciences [DE-AC02-98CH10886]
- BBSRC [BB/L015056/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/L015056/1] Funding Source: researchfish
C. elegans MnSOD-3 has been implicated in the longevity pathway and its mechanism of catalysis is relevant to the aging process and carcinogenesis. The structures of MnSOD-3 provide unique crystallographic evidence of a dynamic region of the tetrameric interface (residues 41-54). We have determined the structure of the MnSOD-3-azide complex to 1.77-angstrom resolution. Analysis of this complex shows that the substrate analog, azide, binds end-on to the manganese center as a sixth ligand and that it ligates directly to a third and new solvent molecule also positioned within interacting distance to the His30 and Tyr34 residues of the substrate access funnel. This is the first structure of a eukaryotic MnSOD-azide complex that demonstrates the extended, uninterrupted hydrogen-bonded network that forms a proton relay incorporating three outer sphere solvent molecules, the substrate analog, the gateway residues, Gln142, and the solvent ligand. This configuration supports the formation and release of the hydrogen peroxide product in agreement with the 5-6-5 catalytic mechanism for MnSOD. The high product dissociation constant k(4) of MnSOD-3 reflects low product inhibition making this enzyme efficient even at high levels of superoxide.
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