Crystal Structure of a Statin Bound to a Class II Hydroxymethylglutaryl-CoA Reductase

School of Biological Sciences, University of Manchester, Oxford Road, United Kingdom.
Journal of Biological Chemistry (Impact Factor: 4.57). 06/2003; 278(22):19933-8. DOI: 10.1074/jbc.M213006200
Source: PubMed


Hydroxymethylglutaryl-CoA (HMG-CoA) reductase is the primary target in the current clinical treatment of hypercholesterolemias with specific inhibitors of the "statin" family. Statins are excellent inhibitors of the class I (human) enzyme but relatively poor inhibitors of the class II enzymes of important bacterial pathogens. To investigate the molecular basis for this difference we determined the x-ray structure of the class II Pseudomonas mevalonii HMG-CoA reductase in complex with the statin drug lovastatin. The structure shows lovastatin bound in the active site and its interactions with residues critically involved in catalysis and substrate binding. Binding of lovastatin also displaces the flap domain of the enzyme, which contains the catalytic residue His-381. Comparison with the structures of statins bound to the human enzyme revealed a similar mode of binding but marked differences in specific interactions that account for the observed differences in affinity. We suggest that these differences might be exploited to develop selective class II inhibitors for use as antibacterial agents against pathogenic microorganisms.

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    • "The pathway enzyme HMG-CoA reductase is of particular interest in this context. It exhibits significant differences in the threedimensional structure and in the sensitivity to inhibition by the active-site inhibitors known as statins (Tabernero et al. 2003). Isopentenyl diphosphate (IPP) isomerase is another important enzyme. "
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    • "But do such differences exist? For HMG-CoA reductase, marked structural differences characterize the class I human enzyme and the class 2 enzyme of a bacterial nonpathogen (Tabernero et al. 2003; Hedl et al. 2004). While at present the only relevant crystal structures are those of HMG-CoA reductase, coordinates are on file for both E. faecalis and human HMG- CoA synthase, and crystallization trials for E. faecalis HMG-CoA reductase have been initiated. "
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