Structural and Kinetic Analysis of Free Methionine-R-sulfoxide Reductase from Staphylococcus aureus CONFORMATIONAL CHANGES DURING CATALYSIS AND IMPLICATIONS FOR THE CATALYTIC AND INHIBITORY MECHANISMS

Title
Structural and Kinetic Analysis of Free Methionine-R-sulfoxide Reductase from Staphylococcus aureus CONFORMATIONAL CHANGES DURING CATALYSIS AND IMPLICATIONS FOR THE CATALYTIC AND INHIBITORY MECHANISMS
Author(s)
김화영봉승민[봉승민]곽근희문진호[문진호]이기석[이기석]김홍석[김홍석]지영민[지영민]
Keywords
FREE METHIONINE-(R)-SULFOXIDE REDUCTASE; ALZHEIMERS-DISEASE; MOLECULAR-GRAPHICS; GAF DOMAIN; OXIDATION; PEPTIDE; PROTEIN; VIRULENCE; EXPRESSION; REVEALS
Issue Date
201008
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Citation
JOURNAL OF BIOLOGICAL CHEMISTRY, v.285, no.32, pp.25044 - 25052
Abstract
Free methionine-R-sulfoxide reductase (fRMsr) reduces free methionine R-sulfoxide back to methionine, but its catalytic mechanism is poorly understood. Here, we have determined the crystal structures of the reduced, substrate-bound, and oxidized forms of fRMsr from Staphylococcus aureus. Our structural and biochemical analyses suggest the catalytic mechanism of fRMsr in which Cys(102) functions as the catalytic residue and Cys(68) as the resolving Cys that forms a disulfide bond with Cys(102).Cys(78), previously thought to be a catalytic Cys, is a non-essential residue for catalytic function. Additionally, our structures provide insights into the enzyme-substrate interaction and the role of active site residues in substrate binding. Structural comparison reveals that conformational changes occur in the active site during catalysis, particularly in the loop of residues 97-106 containing the catalytic Cys(102). We have also crystallized a complex between fRMsr and isopropyl alcohol, which acts as a competitive inhibitor for the enzyme. This isopropyl alcohol-bound structure helps us to understand the inhibitory mechanism of fRMsr. Our structural and enzymatic analyses suggest that a branched methyl group in alcohol seems important for competitive inhibition of the fRMsr due to its ability to bind to the active site.
URI
http://hdl.handle.net/YU.REPOSITORY/23864http://dx.doi.org/10.1074/jbc.M110.103119
ISSN
0021-9258
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의과대학 > 생화학.분자생물학교실 > Articles
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