HDX-MS to map the allosteric site for efavirenz, a drug that stimulates cholesterol-metabolizing P450 CYP46A1 activity

摘要

Cytochrome P450 CYP46A1 is a monotopic enzyme that catalyzes hydroxylation of cholesterol to 24(S)-hydroxycholesterol (24HC), which is responsible for 80% of cholesterol elimination from human brain. FDA-approved efavirenz (EFV) acts as an activator at specific low concentrations, enhancing CYP46A1-mediated 24HC production. CYP46A1 activation by EFV is of high clinical relevance for the treatment of Alzheimer's disease (AD). Mouse models of AD with genetically increased CYP46A1 activity have improvements in memory and learning and reduction in amyloidbeta pathology. HDX-MS revealed that EFV binding induces conformational changes in the active site, making cholesterol binding tighter and the catalysis more efficient.