3HF9

Crystal Structure of Mycobacterium Tuberculosis Proteasome open-gate mutant modified by inhibitor GL1

3HF9 の概要

• エントリーDOI: 10.2210/pdb3hf9/pdb
• 関連するPDBエントリー: 3HFA
• 分子名称: Proteasome (Alpha subunit) PrcA, Proteasome (Beta subunit) PrcB (3 entities in total)
• 機能のキーワード: binding sites, oxazolidin-2-one, mycobacterium tuberculosis, protease inhibitors, proteasome endopeptidase complex, protein subunits, substrate specificity, open gate, mutant, hydrolase, proteasome
• 由来する生物種: Mycobacterium tuberculosis; 詳細
• タンパク質・核酸の鎖数: 56
• 化学式量合計: 1435622.52

構造登録者

Li, D.,Li, H. (登録日: 2009-05-11, 公開日: 2009-09-15, 最終更新日: 2023-11-22)

主引用文献

Lin, G.,Li, D.,de Carvalho, L.P.,Deng, H.,Tao, H.,Vogt, G.,Wu, K.,Schneider, J.,Chidawanyika, T.,Warren, J.D.,Li, H.,Nathan, C.
Inhibitors selective for mycobacterial versus human proteasomes.
Nature, 461:621-626, 2009

PubMed Abstract: Many anti-infectives inhibit the synthesis of bacterial proteins, but none selectively inhibits their degradation. Most anti-infectives kill replicating pathogens, but few preferentially kill pathogens that have been forced into a non-replicating state by conditions in the host. To explore these alternative approaches we sought selective inhibitors of the proteasome of Mycobacterium tuberculosis. Given that the proteasome structure is extensively conserved, it is not surprising that inhibitors of all chemical classes tested have blocked both eukaryotic and prokaryotic proteasomes, and no inhibitor has proved substantially more potent on proteasomes of pathogens than of their hosts. Here we show that certain oxathiazol-2-one compounds kill non-replicating M. tuberculosis and act as selective suicide-substrate inhibitors of the M. tuberculosis proteasome by cyclocarbonylating its active site threonine. Major conformational changes protect the inhibitor-enzyme intermediate from hydrolysis, allowing formation of an oxazolidin-2-one and preventing regeneration of active protease. Residues outside the active site whose hydrogen bonds stabilize the critical loop before and after it moves are extensively non-conserved. This may account for the ability of oxathiazol-2-one compounds to inhibit the mycobacterial proteasome potently and irreversibly while largely sparing the human homologue.

PubMed: 19759536
DOI: 10.1038/nature08357

実験手法

X-RAY DIFFRACTION (2.878 Å)