Structural mechanism for statin inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase.

3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) catalyzes the committed step in cholesterol biosynthesis. HMGR is the target of compounds (HMGR inhibitors, commonly referred to as statins) that are very effective in lowering serum cholesterol levels. These inhibitors have K(i) values in the nanomolar range and are widely prescribed in the treatment of hypercholesterolemia. We have determined structures of this enzyme in complexes with 6 different statins (compactin, simvastatin, fluvastatin, cerivastatin, atorvastatin, and rosuvastatin). The statins occupy a portion of the binding site of HMG-CoA, thus blocking access of this substrate to the active site. The nicotinamide binding pocket of NADP(H) (the second substrate of the enzyme) is unoccupied by the inhibitor molecules. Near the C-terminus of HMGR, several catalytically relevant residues are disordered in the enzyme-statin complexes. The flexibility of these residues is critical for binding with statins; if ordered, they would sterically hinder such binding.