PDBsum entry: 1og2

Electron transport

PDB id: 1og2

Contents

Protein chains

462 a.a. *

Ligands

HEC ×2

Waters ×147

* Residue conservation analysis

PDB id:

1og2

Name:

Electron transport

Title:

Structure of human cytochrome p450 cyp2c9

Structure:

Cytochrome p450 2c9. Chain: a, b. Fragment: soluble domain, residues 30-490. Synonym: (r)-limonene 6-monooxygenase, (s)-limonene 6-monoo (s)-limonene 7-monooxygenase, cypiic9, cytochrome p-450mp, cytochrome p450 mp-4, cytochrome p450 mp-8, cytochrome p450 s-mephenytoin 4-hydroxylase. Ec: 1.14.13.80, 1.14.13.48, 1.14.13.49. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.60Å R-factor: 0.210 R-free: 0.259

Authors:

P.A.Williams,J.Cosme,A.Ward,H.C.Angove,D.Matak Vinkovic, H.Jhoti

Key ref:

P.A.Williams et al. (2003). Crystal structure of human cytochrome P450 2C9 with bound warfarin. Nature, 424, 464-468. PubMed id: 12861225 DOI: 10.1038/nature01862

Date:

23-Apr-03 Release date: 17-Jul-03

Protein chains

P11712  (CP2C9_HUMAN) -  Cytochrome P450 2C9

Seq: 490 a.a.

Struc: 462 a.a.*

* PDB and UniProt seqs differ at 7 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: E.C.1.14.13.48 - (S)-limonene 6-monooxygenase.
• Reaction: ^--(S)-limonene + NADPH + O₂ = ^--trans-carveol + NADP⁺ + H₂O
• Cofactor: Heme-thiolate
• Enzyme class 2: E.C.1.14.13.49 - (S)-limonene 7-monooxygenase.
• Reaction: ^--(S)-limonene + NADPH + O₂ = ^--perillyl alcohol + NADP⁺ + H₂O
• Cofactor: Heme-thiolate
• Enzyme class 3: E.C.1.14.13.80 - (R)-limonene 6-monooxygenase.

Pathway:

• Reaction: ⁺-(R)-limonene + NADPH + O₂ = ⁺-trans-carveol + NADP⁺ + H₂O
• Cofactor: Heme-thiolate

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 Gene Ontology (GO) functional annotation 

• Cellular component: membrane (4 terms)
• Biological process: oxidative demethylation (11 terms)
• Biochemical function: electron carrier activity (13 terms)

reference

DOI no: 10.1038/nature01862

Nature 424:464-468 (2003)

PubMed id: 12861225

Crystal structure of human cytochrome P450 2C9 with bound warfarin.

P.A.Williams, J.Cosme, A.Ward, H.C.Angove, D.Matak Vinković, H.Jhoti.

ABSTRACT

Cytochrome P450 proteins (CYP450s) are membrane-associated haem proteins that metabolize physiologically important compounds in many species of microorganisms, plants and animals. Mammalian CYP450s recognize and metabolize diverse xenobiotics such as drug molecules, environmental compounds and pollutants. Human CYP450 proteins CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 are the major drug-metabolizing isoforms, and contribute to the oxidative metabolism of more than 90% of the drugs in current clinical use. Polymorphic variants have also been reported for some CYP450 isoforms, which has implications for the efficacy of drugs in individuals, and for the co-administration of drugs. The molecular basis of drug recognition by human CYP450s, however, has remained elusive. Here we describe the crystal structure of a human CYP450, CYP2C9, both unliganded and in complex with the anti-coagulant drug warfarin. The structure defines unanticipated interactions between CYP2C9 and warfarin, and reveals a new binding pocket. The binding mode of warfarin suggests that CYP2C9 may undergo an allosteric mechanism during its function. The newly discovered binding pocket also suggests that CYP2C9 may simultaneously accommodate multiple ligands during its biological function, and provides a possible molecular basis for understanding complex drug-drug interactions.

Selected figure(s)

Figure 1.
Figure 1: Structure of P450 CYP2C9. a, Overall fold of CYP2C9, coloured from blue at the N terminus to red at the C terminus. The haem group is depicted as a ball-and-stick model in the centre of the molecule, flanked by helices I and L. There is a slight distortion in helix I, close to the haem. The substrate access channel is widely acknowledged to involve the loops between helices B and C, and helices F and G. The figure was produced using Molscript (http://www.avatar.se/molscript). b, View of Arg 97 and the haem group (shown at the bottom). Arg 97 is held in position by hydrogen bonds (indicated by dashed lines) to the haem propionates and to the carbonyl oxygen atoms of Val 113 and Pro 367. Figures 1b -4b were produced using Aesop 2.5 (M. Noble, unpublished work).

Figure 4.
Figure 4: View of the region of the active site of CYP2C9 that remains available to accommodate additional ligand(s) after S-warfarin. The bound S-warfarin molecule is shown as in Fig. 3. a, A second molecule of S-warfarin has been modelled into the active with the site of hydroxylation closest to the haem iron. b, A known haem binder fluconazole has been modelled into the cavity in a similar conformation to that observed in the complex of CYP51 with fluconazole (Protein Data Bank code 1EA1).

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2003, 424, 464-468) copyright 2003.

Figures were selected by the author.