1PQ2
Crystal Structure of Human Drug Metabolizing Cytochrome P450 2C8
Summary for 1PQ2
| Entry DOI | 10.2210/pdb1pq2/pdb |
| Related | 1DT6 1N6B |
| Descriptor | Cytochrome P450 2C8, PHOSPHATE ION, PROTOPORPHYRIN IX CONTAINING FE, ... (5 entities in total) |
| Functional Keywords | cytochrome p450, cyp2c8, membrane protein, taxol 6-hydroxylase, oxidoreductase |
| Biological source | Homo sapiens (human) |
| Cellular location | Endoplasmic reticulum membrane; Peripheral membrane protein: P10632 |
| Total number of polymer chains | 2 |
| Total formula weight | 109949.11 |
| Authors | Schoch, G.A.,Yano, J.K.,Wester, M.R.,Griffin, K.J.,Stout, C.D.,Johnson, E.F. (deposition date: 2003-06-17, release date: 2004-01-13, Last modification date: 2023-08-16) |
| Primary citation | Schoch, G.A.,Yano, J.K.,Wester, M.R.,Griffin, K.J.,Stout, C.D.,Johnson, E.F. Structure of human microsomal cytochrome P450 2C8. Evidence for a peripheral fatty acid binding site J.Biol.Chem., 279:9497-9503, 2004 Cited by PubMed Abstract: A 2.7-Angstrom molecular structure of human microsomal cytochrome P450 2C8 (CYP2C8) was determined by x-ray crystallography. The membrane protein was modified for crystallization by replacement of the hydrophobic N-terminal transmembrane domain with a short hydrophilic sequence before residue 28. The structure of the native sequence is complete from residue 28 to the beginning of a C-terminal histidine tag used for purification. CYP2C8 is one of the principal hepatic drug-metabolizing enzymes that oxidizes therapeutic drugs such as taxol and cerivastatin and endobiotics such as retinoic acid and arachidonic acid. Consistent with the relatively large size of its preferred substrates, the active site volume is twice that observed for the structure of CYP2C5. The extended active site cavity is bounded by the beta1 sheet and helix F' that have not previously been implicated in substrate recognition by mammalian P450s. CYP2C8 crystallized as a symmetric dimer formed by the interaction of helices F, F', G', and G. Two molecules of palmitic acid are bound in the dimer interface. The dimer is observed in solution, and mass spectrometry confirmed the association of palmitic acid with the enzyme. This novel finding identifies a peripheral binding site in P450s that may contribute to drug-drug interactions in P450 metabolism. PubMed: 14676196DOI: 10.1074/jbc.M312516200 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.7 Å) |
Structure validation
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