Statin inhibition of HMG-CoA reductase: a 3-dimensional view

Atheroscler Suppl. 2003 Mar;4(1):3-8. doi: 10.1016/s1567-5688(03)00003-5.


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.

Publication types

  • Review

MeSH terms

  • Cholesterol / metabolism
  • Coronary Disease / drug therapy
  • Coronary Disease / epidemiology
  • Coronary Disease / metabolism
  • Humans
  • Hydroxymethylglutaryl CoA Reductases / drug effects*
  • Hydroxymethylglutaryl CoA Reductases / metabolism
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
  • Liver / metabolism
  • Receptors, LDL / drug effects
  • Receptors, LDL / metabolism
  • Risk Factors
  • Up-Regulation / drug effects


  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Receptors, LDL
  • Cholesterol
  • Hydroxymethylglutaryl CoA Reductases