Substrate-induced closure of the flap domain in the ternary complex structures provides insights into the mechanism of catalysis by 3-hydroxy-3-methylglutaryl-CoA reductase

3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase is the rate-limiting enz yme and the first committed step in the biosynthesis of cholesterol in mamm als. Ne have determined the crystal structures of two nonproductive ternary complexes of HMG-CoA reductase, HMG-CoA/ NAD(+) and mevalonate/NADH, at 2. 8 Angstrom resolution. In the structure of the Pseudomonas mevalonii apoenz yme, the last 50 residues of the C terminus (the flap domain), including th e catalytic residue His381, were not visible. The structures of the ternary complexes reported here reveal a substrate-induced closing of the flap dom ain that completes the active site and aligns the catalytic histidine proxi mal to the thioester of HMG-CoA. The structures also present evidence that Lys267 is critically involved in catalysis and provide insights into the ca talytic mechanism.