Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis

3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) catalyzes the formation of mevalonate, the committed step in the biosynthesis of sterols and isoprenoi ds. The activity of HMGR is controlled through synthesis, degradation and p hosphorylation to maintain the concentration of mevalonate-derived products . In addition to the physiological regulation of HMGR, the human enzyme has been targeted successfully by drugs in the clinical treatment of high seru m cholesterol levels. Three crystal structures of the catalytic portion of human HMGR in complexes with HMG-CoA, with HMG and Coli, and with HMG, CoA and NADP(+), provide a detailed view of the enzyme active site. Catalytic p ortions of human HMGR form tight tetramers, The crystal structure explains the influence of the enzyme's oligomeric state on the activity and suggests a mechanism for cholesterol sensing. The active site architecture of human HMGR is different from that of bacterial HMGR; this may explain why bindin g of HMGR inhibitors to bacterial HMGRs has not been reported.