title: Membrane position of ibuprofen agrees with suggested access path entrance to cytochrome P450 2C9 active site.
abstract: Cytochrome P450 2C9 (CYP2C9) is a membrane-anchored human microsomal protein involved in the drug metabolism in liver. CYP2C9 consists of an N-terminal transmembrane anchor and a catalytic cytoplasmic domain. While the structure of the catalytic domain is well-known from X-ray experiments, the complete structure and its incorporation into the membrane remains unsolved. We constructed an atomistic model of complete CYP2C9 in a dioleoylphosphatidylcholine membrane and evolved it by molecular dynamics simulations in explicit water on a 100+ ns time-scale. The model agrees well with known experimental data about membrane positioning of cytochromes P450. The entry to the substrate access channel is proposed to be facing the membrane interior while the exit of the product egress channel is situated above the interface pointing toward the water phase. The positions of openings of the substrate access and product egress channels correspond to free energy minima of CYP2C9 substrate ibuprofen and its metabolite in the membrane, respectively.
authors: Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacky University, Olomouc, Czech Republic.
authors: Karel
authors: K
authors: Berka
authors: Tereza
authors: T
authors: Hendrychová
authors: Pavel
authors: P
authors: Anzenbacher
authors: Michal
authors: M
authors: Otyepka
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D065729:Cytochrome P-450 CYP2C9; D006801:Humans; D007052:Ibuprofen / Q000737:chemistry* / Q000378:metabolism*; D008567:Membranes, Artificial; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010713:Phosphatidylcholines / Q000737:chemistry / Q000378:metabolism; D013499:Surface Properties
chemical_list: D008567:Membranes, Artificial; D010713:Phosphatidylcholines; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C017251:1,2-oleoylphosphatidylcholine; D007052:Ibuprofen