PDBsum entry 1u5c

Oxidoreductase

PDB id: 1u5c

Contents

Protein chain

305 a.a. *

Ligands

NAD

BIK

Waters ×132

* Residue conservation analysis

PDB id:

1u5c

Name:

Oxidoreductase

Title:

Plasmodium falciparum lactate dehydrogenase complexed with 3,7- dihydroxynaphthalene-2-carboxylic acid and NAD+

Structure:

L-lactate dehydrogenase. Chain: a. Synonym: ldh-p. Engineered: yes

Source:

Plasmodium falciparum. Malaria parasite p. Falciparum. Organism_taxid: 5833. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Tetramer (from PDB file)

Resolution:

2.65Å R-factor: 0.158 R-free: 0.239

Authors:

R.Conners,A.Cameron,J.Read,F.Schambach,R.B.Sessions,R.L.Brady

Key ref:

R.Conners et al. (2005). Mapping the binding site for gossypol-like inhibitors of Plasmodium falciparum lactate dehydrogenase. Mol Biochem Parasitol, 142, 137-148. PubMed id: 15978953 DOI: 10.1016/j.molbiopara.2005.03.015

Date:

27-Jul-04 Release date: 21-Jun-05

Protein chain

Q27743  (LDH_PLAFD) -  L-lactate dehydrogenase from Plasmodium falciparum (isolate CDC / Honduras)

Seq: 316 a.a.

Struc: 305 a.a.

Enzyme reactions

• Enzyme class: E.C.1.1.1.27 - L-lactate dehydrogenase.
• Reaction: (S)-lactate + NAD⁺ = pyruvate + NADH + H⁺

(S)-lactate + NAD(+) (Bound ligand (Het Group name = NAD) corresponds exactly) = pyruvate + NADH + H(+)

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

reference

DOI no: 10.1016/j.molbiopara.2005.03.015

Mol Biochem Parasitol 142:137-148 (2005)

PubMed id: 15978953

Mapping the binding site for gossypol-like inhibitors of Plasmodium falciparum lactate dehydrogenase.

R.Conners, F.Schambach, J.Read, A.Cameron, R.B.Sessions, L.Vivas, A.Easton, S.L.Croft, R.L.Brady.

ABSTRACT

Gossypol is a di-sesquiterpene natural-product in the form of a functionalised binaphthyl and is isolated from cotton plants. The compound has long been known to exhibit anti-malarial and other biological activities. Previous studies have indicated that compounds of this type target Plasmodium falciparum lactate dehydrogenase (pfLDH), an essential enzyme for energy generation within the parasite. In this study, we report that simple naphthalene-based compounds, the core of the gossypol structure, exhibit weak inhibition of the parasite lactate dehydrogenase. Crystal structures of the complexes formed by binding of these naphthalene-based compounds to their target enzyme have been used to delineate the molecular features likely to form the gossypol binding site. Two modes of binding are observed: one overlapping the pyruvate but not the co-factor site, the other bridging the binding sites for the co-factor nicontinamide group and pyruvate substrate. This latter site encompasses molecular features unique to Plasmodium forms of LDH and is likely to represent the mode of binding for gossypol derivatives that show selectivity for the parasite enzymes. We also report a substrate analogue that unexpectedly binds within the adenine pocket of the co-factor groove. Although these core pharmacophore-like molecules only exhibit low levels of inhibitory activity, these molecular snapshots provide a rational basis for renewed structure-based development of naphthalene-based compounds as anti-malarial agents.