6R6A

Major aspartyl peptidase 1 from C. neoformans

6R6A の概要

• エントリーDOI: 10.2210/pdb6r6a/pdb
• 関連するPDBエントリー: 6R5H 6R61
• 分子名称: Endopeptidase, Pepstatin, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• 機能のキーワード: aspartyl protease, secreted, cryptococcus neoformans, hydrolase
• 由来する生物種: Cryptococcus neoformans var. grubii; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 39448.03

構造登録者

Krystufek, R.,Sacha, P.,Brynda, J.,Konvalinka, J. (登録日: 2019-03-26, 公開日: 2021-04-07, 最終更新日: 2024-11-06)

主引用文献

Krystufek, R.,Sacha, P.,Starkova, J.,Brynda, J.,Hradilek, M.,Tloust'ova, E.,Grzymska, J.,Rut, W.,Boucher, M.J.,Drag, M.,Majer, P.,Hajek, M.,Rezacova, P.,Madhani, H.D.,Craik, C.S.,Konvalinka, J.
Re-emerging Aspartic Protease Targets: Examining Cryptococcus neoformans Major Aspartyl Peptidase 1 as a Target for Antifungal Drug Discovery.
J.Med.Chem., 64:6706-6719, 2021

PubMed Abstract: Cryptococcosis is an invasive infection that accounts for 15% of AIDS-related fatalities. Still, treating cryptococcosis remains a significant challenge due to the poor availability of effective antifungal therapies and emergence of drug resistance. Interestingly, protease inhibitor components of antiretroviral therapy regimens have shown some clinical benefits in these opportunistic infections. We investigated Major aspartyl peptidase 1 (May1), a secreted protease, as a possible target for the development of drugs that act against both fungal and retroviral aspartyl proteases. Here, we describe the biochemical characterization of May1, present its high-resolution X-ray structure, and provide its substrate specificity analysis. Through combinatorial screening of 11,520 compounds, we identified a potent inhibitor of May1 and HIV protease. This dual-specificity inhibitor exhibits antifungal activity in yeast culture, low cytotoxicity, and low off-target activity against host proteases and could thus serve as a lead compound for further development of May1 and HIV protease inhibitors.

PubMed: 34006103
DOI: 10.1021/acs.jmedchem.0c02177

実験手法

X-RAY DIFFRACTION (1.8 Å)