1U5C

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

1U5C の概要

• エントリーDOI: 10.2210/pdb1u5c/pdb
• 関連するPDBエントリー: 1u40 1u4s 1u5a
• 分子名称: L-lactate dehydrogenase, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, 3,7-DIHYDROXY-2-NAPHTHOIC ACID, ... (4 entities in total)
• 機能のキーワード: protein-ligand complex, oxidoreductase
• 由来する生物種: Plasmodium falciparum (malaria parasite P. falciparum)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35713.99

構造登録者

Conners, R.,Cameron, A.,Read, J.,Schambach, F.,Sessions, R.B.,Brady, R.L. (登録日: 2004-07-27, 公開日: 2005-06-21, 最終更新日: 2023-08-23)

主引用文献

Conners, R.,Schambach, F.,Read, J.,Cameron, A.,Sessions, R.B.,Vivas, L.,Easton, A.,Croft, S.L.,Brady, R.L.
Mapping the binding site for gossypol-like inhibitors of Plasmodium falciparum lactate dehydrogenase.
Mol.Biochem.Parasitol., 142:137-148, 2005

PubMed 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.

PubMed: 15978953
DOI: 10.1016/j.molbiopara.2005.03.015

実験手法

X-RAY DIFFRACTION (2.65 Å)