From closed to open: three dynamic states of membrane-bound cytochrome P450 3A4.

ABSTRACT: Cytochrome P450 3A4 (CYP3A4) is a membrane bound monooxygenase. It metabolizes the largest proportion of all orally ingested drugs. Ligands can enter and exit the enzyme through flexible tunnels, which co-determine CYP3A4's ligand promiscuity. The flexibility can be represented by distinct conformational states of the enzyme. However, previous state definitions relied solely on crystal structures. We employed conventional molecular dynamics (cMD) simulations to sample the conformational space of CYP3A4. Five conformationally different crystal structures embedded in a membrane were simulated for 1 µs each. A Markov state model (MSM) coupled with spectral clustering (Robust Perron Cluster Analysis PCCA +) resulted in three distinct states: Two open conformations and an intermediate conformat

SUBMITTER: Spanke VA 

PROVIDER: S-EPMC11913904 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature