1NR6
MICROSOMAL CYTOCHROME P450 2C5/3LVDH COMPLEX WITH DICLOFENAC
Summary for 1NR6
| Entry DOI | 10.2210/pdb1nr6/pdb |
| Related | 1DT6 1N6B |
| Descriptor | CYTOCHROME P450 2C5, SULFATE ION, PROTOPORPHYRIN IX CONTAINING FE, ... (5 entities in total) |
| Functional Keywords | membrane protein, progesterone 21-hydroxylase, benzo(a), pyrene hydroxylase, estradiol 2-hydroxylase, p450, cyp2c5, diclofenac complex, oxidoreductase |
| Biological source | Oryctolagus cuniculus (rabbit) |
| Cellular location | Endoplasmic reticulum membrane (By similarity): P00179 |
| Total number of polymer chains | 1 |
| Total formula weight | 54989.01 |
| Authors | Wester, M.R.,Johnson, E.F.,Stout, C.D. (deposition date: 2003-01-23, release date: 2003-08-12, Last modification date: 2023-08-16) |
| Primary citation | WESTER, M.R.,JOHNSON, E.F.,Marques-Soares, C.,Dijols, S.,Dansette, P.M.,Mansuy, D.,STOUT, C.D. Structure of Mammalian Cytochrome P450 2C5 Complexed with Diclofenac at 2.1 A Resolution: Evidence for an Induced Fit Model of Substrate Binding Biochemistry, 42:9335-9345, 2003 Cited by PubMed Abstract: The structure of the anti-inflammatory drug diclofenac bound in the active site of rabbit microsomal cytochrome P450 2C5/3LVdH was determined by X-ray crystallography to 2.1 A resolution. P450 2C5/3LVdH and the related enzyme 2C5dH catalyze the 4'-hydroxylation of diclofenac with apparent K(m) values of 80 and 57 microM and k(cat) values of 13 and 16 min(-1), respectively. Spectrally determined binding constants are similar to the K(m) values. The structure indicates that the pi-electron system of the dichlorophenyl moiety faces the heme Fe with the 3'- and 4'-carbons located 4.4 and 4.7 A, respectively, from the Fe. The carboxyl moiety of the substrate is hydrogen bonded to a cluster of waters that are also hydrogen bonded to the side chains of N204, K241, S289, and D290 as well as the backbone of the protein. The proximity of the diclofenac carboxylate to the side chain of D290 together with an increased binding affinity at lower pH suggests that diclofenac is protonated when bound to the enzyme. The structure exhibits conformational changes indicative of an adaptive fit to the substrate reflecting both the hydration and size of the substrate. These results indicate how structurally diverse substrates are recognized by drug-metabolizing P450 enzymes. PubMed: 12899620DOI: 10.1021/bi034556l PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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