Structural mechanism for statin inhibition of HMG-CoA reductase

Science. 2001 May 11;292(5519):1160-4. doi: 10.1126/science.1059344.


HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase (HMGR) catalyzes the committed step in cholesterol biosynthesis. Statins are HMGR inhibitors with inhibition constant values in the nanomolar range that effectively lower serum cholesterol levels and are widely prescribed in the treatment of hypercholesterolemia. We have determined structures of the catalytic portion of human HMGR complexed with six different statins. The statins occupy a portion of the binding site of HMG-CoA, thus blocking access of this substrate to the active site. Near the carboxyl terminus of HMGR, several catalytically relevant residues are disordered in the enzyme-statin complexes. If these residues were not flexible, they would sterically hinder statin binding.

MeSH terms

  • Acyl Coenzyme A / antagonists & inhibitors
  • Acyl Coenzyme A / metabolism
  • Anticholesteremic Agents / chemistry*
  • Anticholesteremic Agents / metabolism
  • Anticholesteremic Agents / pharmacology*
  • Binding Sites
  • Catalytic Domain
  • Crystallography, X-Ray
  • Humans
  • Hydrogen Bonding
  • Hydroxymethylglutaryl CoA Reductases / chemistry*
  • Hydroxymethylglutaryl CoA Reductases / metabolism*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / chemistry*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / metabolism
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Models, Molecular
  • Pliability
  • Protein Binding
  • Protein Structure, Secondary


  • Acyl Coenzyme A
  • Anticholesteremic Agents
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • 3-hydroxy-3-methylglutaryl-coenzyme A
  • Hydroxymethylglutaryl CoA Reductases

Associated data

  • PDB/1HW8
  • PDB/1HW9
  • PDB/1HWI
  • PDB/1HWJ
  • PDB/1HWK
  • PDB/1HWL