6OCW

Crystal Structure of Mycobacterium tuberculosis Proteasome in Complex with Phenylimidazole-based Inhibitor A85

6OCW の概要

• エントリーDOI: 10.2210/pdb6ocw/pdb
• 分子名称: Proteasome subunit alpha, Proteasome subunit beta, DIMETHYLFORMAMIDE, ... (6 entities in total)
• 機能のキーワード: mycobacterium tuberculosis, proteasome inhibitor, phenylimidazole, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv); 詳細
• タンパク質・核酸の鎖数: 28
• 化学式量合計: 716902.73

構造登録者

Hsu, H.C.,Li, H. (登録日: 2019-03-25, 公開日: 2019-10-09, 最終更新日: 2023-10-11)

主引用文献

Zhan, W.,Hsu, H.C.,Morgan, T.,Ouellette, T.,Burns-Huang, K.,Hara, R.,Wright, A.G.,Imaeda, T.,Okamoto, R.,Sato, K.,Michino, M.,Ramjee, M.,Aso, K.,Meinke, P.T.,Foley, M.,Nathan, C.F.,Li, H.,Lin, G.
Selective Phenylimidazole-Based Inhibitors of theMycobacterium tuberculosisProteasome.
J.Med.Chem., 62:9246-9253, 2019

PubMed Abstract: Proteasomes of pathogenic microbes have become attractive targets for anti-infectives. Coevolving with its human host, (Mtb) has developed mechanisms to resist host-imposed nitrosative and oxidative stresses. Genetic deletion or pharmacological inhibition of the Mtb proteasome (Mtb20S) renders nonreplicating Mtb susceptible to reactive nitrogen species in vitro and unable to survive in the lungs of mice, validating the Mtb proteasome as a promising target for anti-Mtb agents. Using a structure-guided and flow chemistry-enabled study of structure-activity relationships, we developed phenylimidazole-based peptidomimetics that are highly potent for Mtb20S. X-ray structures of selected compounds with Mtb20S shed light on their selectivity for mycobacterial over human proteasomes.

PubMed: 31560200
DOI: 10.1021/acs.jmedchem.9b01187

実験手法

X-RAY DIFFRACTION (2.6 Å)