title: Effect of cholesterol on the structure of membrane-attached cytochrome P450 3A4.
abstract: Cholesterol is a widely researched component of biological membranes that significantly influences membrane properties. Human cytochrome P450 3A4 (CYP3A4) is an important drug-metabolizing enzyme, wherein the catalytic domain is attached to a membrane by an N-terminal α-helical transmembrane anchor. We analyzed the behavior of CYP3A4 immersed in a 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) membrane with various amounts of cholesterol. The presence of cholesterol caused ordering and thickening of the membrane and led to greater immersion and inclination of CYP3A4 toward the membrane. Cholesterol also lowered the flexibility of and tended to concentrate around membrane-immersed parts of CYP3A4. Further, the pattern of the CYP3A4 active-site access channels was altered in the presence of cholesterol. In summary, cholesterol in the membrane affected the positioning and structural features of CYP3A4, which in turn may have implications for the activity of this enzyme in various membranes and membrane parts with different cholesterol content.
authors: Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacký University Olomouc, tř. 17. listopadu 12, 771 46, Olomouc, Czech Republic.
authors: Veronika
authors: V
authors: Navrátilová
authors: Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacký University Olomouc, tř. 17. listopadu 12, 771 46, Olomouc, Czech Republic.
authors: Markéta
authors: M
authors: Paloncýová
authors: Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacký University Olomouc, tř. 17. listopadu 12, 771 46, Olomouc, Czech Republic.
authors: Michaela
authors: M
authors: Kajšová
authors: Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacký University Olomouc, tř. 17. listopadu 12, 771 46, Olomouc, Czech Republic.
authors: Karel
authors: K
authors: Berka
authors: Regional Centre of Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacký University Olomouc, tř. 17. listopadu 12, 771 46, Olomouc, Czech Republic.
authors: Michal
authors: M
authors: Otyepka
mesh_terms: D020134:Catalytic Domain; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D002784:Cholesterol / Q000737:chemistry* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D010713:Phosphatidylcholines / Q000737:chemistry; D011487:Protein Conformation
chemical_list: D010713:Phosphatidylcholines; D002784:Cholesterol; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C017251:1,2-oleoylphosphatidylcholine