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

• DOI: 10.1073/pnas.96.13.7167
• Publication Date: 2002-07-26T14:41:48Z
• Authors: Lydia Tabernero; Daniel A. Bochar; Victor W. Rodwell; Cynthia V. Stauff...
• Keywords: Ternary complex; Coenzyme A; Thioester; Residue (chemistry)

3-hydroxy-3-methylglutaryl–CoA (HMG-CoA) reductase is the rate-limiting enzyme and first committed step in biosynthesis of cholesterol mammals. We have determined crystal structures two nonproductive ternary complexes HMG-CoA reductase, HMG-CoA/NAD + mevalonate/NADH, at 2.8 Å resolution. In structure Pseudomonas mevalonii apoenzyme, last 50 residues C terminus (the flap domain), including catalytic residue His381, were not visible. The reported here reveal a substrate-induced closing domain that completes active site aligns histidine proximal to thioester HMG-CoA. also present evidence Lys267 critically involved catalysis provide insights into mechanism.