3LSY

Enoyl-ACP Reductase from Plasmodium falciparum (PfENR) in complex with triclosan variant T0

Summary for 3LSY

• Entry DOI: 10.2210/pdb3lsy/pdb
• Related: 1UH5 1V35 1ZSN 1ZXL 2OL4 2OOS 3LT0 3LT1 3LT2 3LT4
• Descriptor: Enoyl-ACP reductase, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, 3-hydroxy-4-phenoxybenzaldehyde, ... (4 entities in total)
• Functional Keywords: triclosan, triclosan variant, enoyl-acp reductase, oxidoreductase, p.falciparum
• Biological source: Plasmodium falciparum
• Total number of polymer chains: 2
• Total formula weight: 76243.65

Authors

Maity, K.,Bhargav, S.P.,Surolia, N.,Surolia, A.,Suguna, K. (deposition date: 2010-02-14, release date: 2010-06-16, Last modification date: 2023-11-01)

Primary citation

Maity, K.,Bhargav, S.P.,Sankaran, B.,Surolia, N.,Surolia, A.,Suguna, K.
X-ray crystallographic analysis of the complexes of enoyl acyl carrier protein reductase of Plasmodium falciparum with triclosan variants to elucidate the importance of different functional groups in enzyme inhibition
Iubmb Life, 62:467-476, 2010

PubMed Abstract: Triclosan, a well-known inhibitor of Enoyl Acyl Carrier Protein Reductase (ENR) from several pathogenic organisms, is a promising lead compound to design effective drugs. We have solved the X-ray crystal structures of Plasmodium falciparum ENR in complex with triclosan variants having different substituted and unsubstituted groups at different key functional locations. The structures revealed that 4 and 2' substituted compounds have more interactions with the protein, cofactor, and solvents when compared with triclosan. New water molecules were found to interact with some of these inhibitors. Substitution at the 2' position of triclosan caused the relocation of a conserved water molecule, leading to an additional hydrogen bond with the inhibitor. This observation can help in conserved water-based inhibitor design. 2' and 4' unsubstituted compounds showed a movement away from the hydrophobic pocket to compensate for the interactions made by the halogen groups of triclosan. This compound also makes additional interactions with the protein and cofactor which compensate for the lost interactions due to the unsubstitution at 2' and 4'. In cell culture, this inhibitor shows less potency, which indicates that the chlorines at 2' and 4' positions increase the ability of the inhibitor to cross multilayered membranes. This knowledge helps us to modify the different functional groups of triclosan to get more potent inhibitors.

PubMed: 20503440
DOI: 10.1002/iub.327

Experimental method

X-RAY DIFFRACTION (2.85 Å)