Cytochromeâ P450â Induced Ordering of Microsomal Membranes Modulates Affinity for Drugs

Abstract

Although membrane environment is known to boost drug metabolism by mammalian cytochromeâ P450s, the factors that stabilize the structural folding and enhance protein function are unclear. In this study, we use peptideâ based lipid nanodiscs to â trapâ the lipid boundaries of microsomal cytochromeâ P450 2B4. We report the first evidence that CYP2B4 is able to induce the formation of raft domains in a biomimetic compound of the endoplasmic reticulum. NMR experiments were used to identify and quantitatively determine the lipids present in nanodiscs. A combination of biophysical experiments and molecular dynamics simulations revealed a sphingomyelin binding region in CYP2B4. The proteinâ induced lipid raft formation increased the thermal stability of P450 and dramatically altered ligand binding kinetics of the hydrophilic ligand BHT. These results unveil membrane/protein dynamics that contribute to the delicate mechanism of redox catalysis in lipid membrane.Redoxkatalyse in der Lipidmembran: Eine neue Anwendung von Peptidnanoscheiben zeigt, dass Cytochrom P450 2B4 die Bildung von Lipidâ Raftâ Domänen in einer biomimetischen Verbindung des endoplasmatischen Retikulums (ER) induzieren kann. Die proteininduzierten Lipidflöà e steigern die thermische Stabilität von Cytochrom P450 und modulieren die Ligandenbindungskinetik des hydrophilen BHTâ Liganden.