2Q9F
Crystal structure of human cytochrome P450 46A1 in complex with cholesterol-3-sulphate
Summary for 2Q9F
| Entry DOI | 10.2210/pdb2q9f/pdb |
| Related | 2q9g |
| Descriptor | Cytochrome P450 46A1, PHOSPHATE ION, PROTOPORPHYRIN IX CONTAINING FE, ... (6 entities in total) |
| Functional Keywords | cyp46a1, p450 46a1, p450, monooxygenase, cholesterol metabolic enzyme, oxidoreductase, heme, cholesterol-3-sulphate |
| Biological source | Homo sapiens (human) |
| Cellular location | Endoplasmic reticulum membrane; Single-pass membrane protein: Q9Y6A2 |
| Total number of polymer chains | 1 |
| Total formula weight | 53855.82 |
| Authors | White, M.A.,Mast, N.V.,Johnson, E.F.,Stout, C.D.,Pikuleva, I.A. (deposition date: 2007-06-12, release date: 2008-06-17, Last modification date: 2024-02-21) |
| Primary citation | Mast, N.,White, M.A.,Bjorkhem, I.,Johnson, E.F.,Stout, C.D.,Pikuleva, I.A. Crystal structures of substrate-bound and substrate-free cytochrome P450 46A1, the principal cholesterol hydroxylase in the brain. Proc.Natl.Acad.Sci.Usa, 105:9546-9551, 2008 Cited by PubMed Abstract: By converting cholesterol to 24S-hydroxycholesterol, cytochrome P450 46A1 (CYP46A1) initiates the major pathway for cholesterol removal from the brain. Two crystal structures of CYP46A1 were determined. First is the 1.9-A structure of CYP46A1 complexed with a high-affinity substrate cholesterol 3-sulfate (CH-3S). The second structure is that of the substrate-free CYP46A1 at 2.4-A resolution. CH-3S is bound in the productive orientation and occupies the entire length of the banana-shaped hydrophobic active-site cavity. A unique helix B'-C loop insertion (residues 116-120) contributes to positioning cholesterol for oxygenation catalyzed by CYP46A1. A comparison with the substrate-free structure reveals substantial substrate-induced conformational changes in CYP46A1 and suggests that structurally distinct compounds could bind in the enzyme active site. In vitro assays were performed to characterize the effect of different therapeutic agents on cholesterol hydroxylase activity of purified full-length recombinant CYP46A1, and several strong inhibitors and modest coactivators of CYP46A1 were identified. Structural and biochemical data provide evidence that CYP46A1 activity could be altered by exposure to some therapeutic drugs and potentially other xenobiotics. PubMed: 18621681DOI: 10.1073/pnas.0803717105 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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