PDBsum entry 1suo

Oxidoreductase

PDB id: 1suo

Contents

Protein chain

465 a.a. *

Ligands

HEM-CPZ

Waters ×190

* Residue conservation analysis

PDB id:

1suo

Name:

Oxidoreductase

Title:

Structure of mammalian cytochrome p450 2b4 with bound 4-(4- chlorophenyl)imidazole

Structure:

Cytochrome p450 2b4. Chain: a. Synonym: cypiib4, p450-lm2, isozyme 2, p450 types b0 and b1. Engineered: yes. Mutation: yes. Other_details: cys 436 binds heme iron. 4-(4-chlorophenyl)imidazole is bound in the active site coordinating to the heme iron as the sixth ligand.

Source:

Oryctolagus cuniculus. Rabbit. Organism_taxid: 9986. Gene: cyp2b4. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.90Å R-factor: 0.215 R-free: 0.239

Authors:

E.E.Scott,M.A.White,Y.A.He,E.F.Johnson,C.D.Stout,J.R.Halpert

Key ref:

E.E.Scott et al. (2004). Structure of mammalian cytochrome P450 2B4 complexed with 4-(4-chlorophenyl)imidazole at 1.9-A resolution: insight into the range of P450 conformations and the coordination of redox partner binding. J Biol Chem, 279, 27294-27301. PubMed id: 15100217 DOI: 10.1074/jbc.M403349200

Date:

26-Mar-04 Release date: 20-Jul-04

Protein chain

P00178  (CP2B4_RABIT) -  Cytochrome P450 2B4 from Oryctolagus cuniculus

Seq: 491 a.a.

Struc: 465 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.1.14.14.1 - unspecific monooxygenase.
• Reaction: an organic molecule + reduced [NADPH--hemoprotein reductase] + O2 = an alcohol + oxidized [NADPH--hemoprotein reductase] + H2O + H⁺
• Cofactor: Heme-thiolate

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

Added reference

DOI no: 10.1074/jbc.M403349200

J Biol Chem 279:27294-27301 (2004)

PubMed id: 15100217

Structure of mammalian cytochrome P450 2B4 complexed with 4-(4-chlorophenyl)imidazole at 1.9-A resolution: insight into the range of P450 conformations and the coordination of redox partner binding.

E.E.Scott, M.A.White, Y.A.He, E.F.Johnson, C.D.Stout, J.R.Halpert.

ABSTRACT

A 1.9-A molecular structure of the microsomal cytochrome P450 2B4 with the specific inhibitor 4-(4-chlorophenyl)imidazole (CPI) in the active site was determined by x-ray crystallography. In contrast to the previous experimentally determined 2B4 structure, this complex adopted a closed conformation similar to that observed for the mammalian 2C enzymes. The differences between the open and closed structures of 2B4 were primarily limited to the lid domain of helices F through G, helices B' and C, the N terminus of helix I, and the beta(4) region. These large-scale conformational changes were generally due to the relocation of conserved structural elements toward each other with remarkably little remodeling at the secondary structure level. For example, the F' and G' helices were maintained with a sharp turn between them but are placed to form the exterior ceiling of the active site in the CPI complex. CPI was closely surrounded by residues from substrate recognition sites 1, 4, 5, and 6 to form a small, isolated hydrophobic cavity. The switch from open to closed conformation dramatically relocated helix C to a more proximal position. As a result, heme binding interactions were altered, and the putative NADPH-cytochrome P450 reductase binding site was reformed. This suggests a structural mechanism whereby ligand-induced conformational changes may coordinate catalytic activity. Comparison of the 2B4/CPI complex with the open 2B4 structure yields insights into the dynamics involved in substrate access, tight inhibitor binding, and coordination of substrate and redox partner binding.

Selected figure(s)

Figure 2.
Divergent (walleye) stereo view of cytochrome P450 2B4dH(H226Y) with CPI bound. The sequence can be traced from the blue N terminus to the red C terminus. Major helices and termini are labeled. Heme and CPI are shown in red and cyan sticks, respectively. Images generated using PyMOL (www.pymol.org) (41) unless otherwise credited.

Figure 7.
Changes in the position of the C helix and heme ligation upon CPI binding shown in divergent (walleye) stereo. Residues in helix C (ribbon) alter positions significantly between the 2B4 open (green) and the CPI closed (blue) conformations, resulting in the loss of a hydrogen bond to the D ring propionate in the open conformation. Hydrogen bonds between the D ring propionate and helix C residues are indicated by dashed lines. Residues Arg-98 (R98), Ser-430 (S430), Arg-434 (R434), and His-369 (H369) have smaller changes in their positions and are labeled once near the base of the side chain.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 27294-27301) copyright 2004.

Figures were selected by an automated process.