Statin inhibition of HMG-CoA reductase: a 3-dimensional view.
Statins act by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and thereby reducing cholesterol synthesis. In X-ray crystallographic studies, we have determined the structures of the catalytic portions of the enzyme in complex with statin molecules. These studies show that the HMG-like moiety of statin molecules occupy the HMG binding site of the enzyme, with the hydrophobic groups of the statins occupying a binding site exposed by movement of flexible helices in the enzyme catalytic domain. In addition to bonds formed by the HMG-like moiety, statins exhibit different types and numbers of binding interactions in association with structural differences. Type 1 statins (e.g., simvastatin) exhibit binding via a decalin ring structure, and type 2 statins (e.g., rosuvastatin, atorvastatin, fluvastatin) exhibit additional binding via their fluorophenyl group. Rosuvastatin and atorvastatin exhibit hydrogen bonds absent from other type 2 statins; rosuvastatin exhibits a unique bond via its electronegative sulfone group. Differences in statin structure and binding characteristics may partially contribute to differences in potency of HMG-CoA reductase inhibition and other pharmacologic properties.
Istvan
Eva
E
Department of Molecular Microbiology, Howard Hughes Medical Institute, Washington University School of Medicine, Campus Box 8230, 660 South Euclid Avenue, St. Louis, MO 63110, USA. istvan@borcim.wustl.edu
D002784:Cholesterol / Q000378:metabolism; D003327:Coronary Disease / Q000188:drug therapy / Q000453:epidemiology / Q000378:metabolism; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000187:drug effects* / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008099:Liver / Q000378:metabolism; D011973:Receptors, LDL / Q000187:drug effects / Q000378:metabolism; D012307:Risk Factors; D015854:Up-Regulation / Q000187:drug effects
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011973:Receptors, LDL; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases