6Y91

Crystal structure of malate dehydrogenase from Plasmodium Falciparum in complex with NADH

6Y91 の概要

• エントリーDOI: 10.2210/pdb6y91/pdb
• 関連するPDBエントリー: 5nfr 6r8g
• 分子名称: Malate dehydrogenase, NICOTINAMIDE-ADENINE-DINUCLEOTIDE (3 entities in total)
• 機能のキーワード: oxidoreductase
• 由来する生物種: Plasmodium falciparum
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 144105.39

構造登録者

Romero, A.R.,Calderone, V.,Gentili, M.,Lunev, S.,Groves, M.,Popowicz, G.,Domling, A.,Sattler, M. (登録日: 2020-03-06, 公開日: 2021-03-31, 最終更新日: 2024-01-24)

主引用文献

Reyes Romero, A.,Lunev, S.,Popowicz, G.M.,Calderone, V.,Gentili, M.,Sattler, M.,Plewka, J.,Taube, M.,Kozak, M.,Holak, T.A.,Domling, A.S.S.,Groves, M.R.
A fragment-based approach identifies an allosteric pocket that impacts malate dehydrogenase activity.
Commun Biol, 4:949-949, 2021

PubMed Abstract: Malate dehydrogenases (MDHs) sustain tumor growth and carbon metabolism by pathogens including Plasmodium falciparum. However, clinical success of MDH inhibitors is absent, as current small molecule approaches targeting the active site are unselective. The presence of an allosteric binding site at oligomeric interface allows the development of more specific inhibitors. To this end we performed a differential NMR-based screening of 1500 fragments to identify fragments that bind at the oligomeric interface. Subsequent biophysical and biochemical experiments of an identified fragment indicate an allosteric mechanism of 4-(3,4-difluorophenyl) thiazol-2-amine (4DT) inhibition by impacting the formation of the active site loop, located >30 Å from the 4DT binding site. Further characterization of the more tractable homolog 4-phenylthiazol-2-amine (4PA) and 16 other derivatives are also reported. These data pave the way for downstream development of more selective molecules by utilizing the oligomeric interfaces showing higher species sequence divergence than the MDH active site.

PubMed: 34376783
DOI: 10.1038/s42003-021-02442-1

実験手法

X-RAY DIFFRACTION (2.5 Å)