PDBsum entry 2w0b

Oxidoreductase

PDB id: 2w0b

Contents

Protein chain

440 a.a. *

Ligands

HEM-CMW

Waters ×380

* Residue conservation analysis

PDB id:

2w0b

Name:

Oxidoreductase

Title:

Cyp51 of m. Tuberculosis bound to an inhibitor 3-{[(4-methylphenyl) sulfonyl]amino}propyl pyridin-4-ylcarbamate

Structure:

Cytochrome p450 51. Chain: a. Synonym: cyp51, cypli, p450-lia1, sterol 14-alpha demethylase, lanosterol 14-alpha demethylase, p450-14dm. Engineered: yes. Mutation: yes. Other_details: 4xhis tag at thE C-terminus

Source:

Mycobacterium tuberculosis. Organism_taxid: 83332. Strain: h37rv. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.56Å R-factor: 0.168 R-free: 0.201

Authors:

L.M.Podust

Key ref:

C.K.Chen et al. (2009). Trypanosoma cruzi CYP51 inhibitor derived from a Mycobacterium tuberculosis screen hit. Plos Negl Trop Dis, 3, e372. PubMed id: 19190730

Date:

12-Aug-08 Release date: 20-Jan-09

Protein chain

P9WPP9  (CP51_MYCTU) -  Sterol 14alpha-demethylase from Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)

Seq: 451 a.a.

Struc: 440 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.1.14.15.36 - sterol 14alpha-demethylase (ferredoxin).
• Reaction: a 14alpha-methyl steroid + 6 reduced [2Fe-2S]-[ferredoxin] + 3 O2 + 5 H⁺ = a Delta₁₄ steroid + formate + 6 oxidized [2Fe-2S]-[ferredoxin] + 4 H2O

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

Added reference

Plos Negl Trop Dis 3:e372 (2009)

PubMed id: 19190730

Trypanosoma cruzi CYP51 inhibitor derived from a Mycobacterium tuberculosis screen hit.

C.K.Chen, P.S.Doyle, L.V.Yermalitskaya, Z.B.Mackey, K.K.Ang, J.H.McKerrow, L.M.Podust.

ABSTRACT

BACKGROUND: The two front-line drugs for chronic Trypanosoma cruzi infections are limited by adverse side-effects and declining efficacy. One potential new target for Chagas' disease chemotherapy is sterol 14alpha-demethylase (CYP51), a cytochrome P450 enzyme involved in biosynthesis of membrane sterols. METHODOLOGY/PRINCIPAL FINDING: In a screening effort targeting Mycobacterium tuberculosis CYP51 (CYP51(Mt)), we previously identified the N-[4-pyridyl]-formamide moiety as a building block capable of delivering a variety of chemotypes into the CYP51 active site. In that work, the binding modes of several second generation compounds carrying this scaffold were determined by high-resolution co-crystal structures with CYP51(Mt). Subsequent assays against the CYP51 orthologue in T. cruzi, CYP51(Tc), demonstrated that two of the compounds tested in the earlier effort bound tightly to this enzyme. Both were tested in vitro for inhibitory effects against T. cruzi and the related protozoan parasite Trypanosoma brucei, the causative agent of African sleeping sickness. One of the compounds had potent, selective anti-T. cruzi activity in infected mouse macrophages. Cure of treated host cells was confirmed by prolonged incubation in the absence of the inhibiting compound. Discrimination between T. cruzi and T. brucei CYP51 by the inhibitor was largely based on the variability (phenylalanine versus isoleucine) of a single residue at a critical position in the active site. CONCLUSIONS/SIGNIFICANCE: CYP51(Mt)-based crystal structure analysis revealed that the functional groups of the two tightly bound compounds are likely to occupy different spaces in the CYP51 active site, suggesting the possibility of combining the beneficial features of both inhibitors in a third generation of compounds to achieve more potent and selective inhibition of CYP51(Tc).