PDBsum entry 4ige

Oxidoreductase/oxidoreductase inhibitor

PDB id: 4ige

Contents

Protein chains

284 a.a.

Ligands

CHJ ×2

NAD ×2

GOL ×4

SO4 ×2

Waters ×276

PDB id:

4ige

Name:

Oxidoreductase/oxidoreductase inhibitor

Title:

Crystal structure of plasmodium falciparum fabi complexed with NAD and inhibitor 7-(4-chloro-2-hydroxyphenoxy)-4-methyl-2h-chromen-2-one

Structure:

Enoyl-acyl carrier reductase. Chain: a, b. Fragment: c-terminal fragment, unp residues 96-432. Engineered: yes

Source:

Plasmodium falciparum. Organism_taxid: 36329. Strain: 3d7. Gene: pfenr, pff0730c. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.15Å R-factor: 0.164 R-free: 0.202

Authors:

D.Kostrewa,R.Perozzo

Key ref:

F.Belluti et al. (2013). Design, synthesis, and biological and crystallographic evaluation of novel inhibitors of Plasmodium falciparum enoyl-ACP-reductase (PfFabI). J Med Chem, 56, 7516-7526. PubMed id: 24063369 DOI: 10.1021/jm400637m

Date:

17-Dec-12 Release date: 06-Nov-13

Protein chains

C6KSZ2  (C6KSZ2_PLAF7) -  Enoyl-acyl carrier reductase from Plasmodium falciparum (isolate 3D7)

Seq: 432 a.a.

Struc: 284 a.a.

Enzyme reactions

• Enzyme class: E.C.1.3.1.9 - enoyl-[acyl-carrier-protein] reductase (NADH).
• Reaction: a 2,3-saturated acyl-[ACP] + NAD⁺ = a (2E)-enoyl-[ACP] + NADH + H⁺

2,3-saturated acyl-[ACP] + NAD(+) (Bound ligand (Het Group name = NAD) corresponds exactly) = (2E)-enoyl-[ACP] + NADH + H(+)

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

Added reference

DOI no: 10.1021/jm400637m

J Med Chem 56:7516-7526 (2013)

PubMed id: 24063369

Design, synthesis, and biological and crystallographic evaluation of novel inhibitors of Plasmodium falciparum enoyl-ACP-reductase (PfFabI).

F.Belluti, R.Perozzo, L.Lauciello, F.Colizzi, D.Kostrewa, A.Bisi, S.Gobbi, A.Rampa, M.L.Bolognesi, M.Recanatini, R.Brun, L.Scapozza, A.Cavalli.

ABSTRACT

Malaria, a disease of worldwide significance, is responsible for over one million deaths annually. The liver-stage of Plasmodium's life cycle is the first, obligatory, but clinically silent step in malaria infection. The P. falciparum type II fatty acid biosynthesis pathway (PfFAS-II) has been found to be essential for complete liver-stage development and has been regarded as a potential antimalarial target for the development of drugs for malaria prophylaxis and liver-stage eradication. In this paper, new coumarin-based triclosan analogues are reported and their biological profile is explored in terms of inhibitory potency against enzymes of the PfFAS-II pathway. Among the tested compounds, 7 and 8 showed the highest inhibitory potency against Pf enoyl-ACP-reductase (PfFabI), followed by 15 and 3. Finally, we determined the crystal structures of compounds 7 and 11 in complex with PfFabI to identify their mode of binding and to confirm outcomes of docking simulations.