Structural mechanism for statin inhibition of HMG-CoA reductase

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 lo wer serum cholesterol levels and are widely prescribed in the treatment of hypercholesterolemia. We have determined structures of the catalytic portio n 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 substr ate to the active site. Near the carboxyl terminus of HMGR, several catalyt ically relevant residues are disordered in the enzyme-statin complexes. If these residues were not flexible, they would sterically hinder statin bindi ng.