5DRI

Crystal structure of Mycobacterium tuberculosis malate synthase in complex with 2-hydroxy-4-(1H-indol-5-yl)-4-oxobut-2-enoic acid inhibitor

5DRI の概要

• エントリーDOI: 10.2210/pdb5dri/pdb
• 関連するPDBエントリー: 5DRC
• 分子名称: Malate synthase G, MAGNESIUM ION, (2Z)-2-hydroxy-4-(1H-indol-5-yl)-4-oxobut-2-enoic acid, ... (4 entities in total)
• 機能のキーワード: acetyltransferase, transferase
• 由来する生物種: Mycobacterium tuberculosis
• 細胞内の位置: Cytoplasm : A5U3K4
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 80712.24

構造登録者

Krieger, I.V.,Huang, H.-L.,Sacchettini, J.C. (登録日: 2015-09-15, 公開日: 2016-09-28, 最終更新日: 2023-09-27)

主引用文献

Huang, H.L.,Krieger, I.V.,Parai, M.K.,Gawandi, V.B.,Sacchettini, J.C.
Mycobacterium tuberculosis Malate Synthase Structures with Fragments Reveal a Portal for Substrate/Product Exchange.
J. Biol. Chem., 291:27421-27432, 2016

PubMed Abstract: Fragment screening and high throughput screening are complementary approaches that combine with structural biology to explore the binding capabilities of an active site. We have used a fragment-based approach on malate synthase (GlcB) from Mycobacterium tuberculosis and discovered several novel binding chemotypes. In addition, the crystal structures of GlcB in complex with these fragments indicated conformational changes in the active site that represent the enzyme conformations during catalysis. Additional structures of the complex with malate and of the apo form of GlcB supported that hypothesis. Comparative analysis of GlcB structures in complex with 18 fragments allowed us to characterize the preferred chemotypes and their binding modes. The fragment structures showed a hydrogen bond to the backbone carbonyl of Met-631. We successfully incorporated an indole group from a fragment into an existing phenyl-diketo acid series. The resulting indole-containing inhibitor was 100-fold more potent than the parent phenyl-diketo acid with an IC value of 20 nm.

PubMed: 27738104
DOI: 10.1074/jbc.M116.750877

実験手法

X-RAY DIFFRACTION (2.8 Å)