9PRF

Crystal structure of E.coli DsbA in-complex with analogue 6

これはPDB形式変換不可エントリーです。

9PRF の概要

• エントリーDOI: 10.2210/pdb9prf/pdb
• 分子名称: Thiol:disulfide interchange protein DsbA, N-[3-(3-{[(2S)-2-hydroxybutyl]amino}-3-oxoprop-1-yn-1-yl)phenyl]-5-methyl-1,2-oxazole-3-carboxamide, N-[3-(3-{[(2R)-2-hydroxybutyl]amino}-3-oxoprop-1-yn-1-yl)phenyl]-5-methyl-1,2-oxazole-3-carboxamide, ... (4 entities in total)
• 機能のキーワード: oxidoreductase, oxidoreductase inhibitor
• 由来する生物種: Escherichia coli
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 43075.78

構造登録者

Balaji, G.R.,Ilyichova, O.V.,Tasdan, Y.,Akhtar, N.,Scanlon, M.J. (登録日: 2025-07-24, 公開日: 2026-03-25)

主引用文献

Tasdan, Y.,Balaji, G.R.,Davidson, J.,Akhtar, N.,Ilyichova, O.,Guetzoyan, L.J.,Chandrashekaran, I.R.,Alwan, W.,Cobb, H.,Gunzburg, M.J.,Hasanzada, A.,Roughley, S.D.,Murray, J.B.,Thai, V.C.,Cliff, T.,Kahler, C.M.,Mohanty, B.,Capuano, B.,Doak, B.C.,Scanlon, M.J.
Exploiting a Cryptic Pocket in DsbA through Structure-Guided Parallel Synthesis and Direct-to-Biology Screening.
J.Med.Chem., 2026

PubMed Abstract: Antibacterial resistance is a major global health problem, causing an increasing number of deaths worldwide. DsbA, a bacterial oxidoreductase enzyme, is pivotal for the correct folding and activity of virulence factors in bacteria. Inhibiting DsbA presents a promising avenue for developing antivirulence compounds and combating bacterial resistance. The enzyme's structure features two ligand-binding sites: a hydrophobic groove that is the binding site for natural peptide substrates and a "cryptic pocket" enclosed within the protein, which has recently been identified as a target for ligand design. In this study, we report the elaboration of a fragment from within the enclosed cryptic pocket into the hydrophobic groove of DsbA, using X-ray crystallography-guided structure-based design and parallel synthesis coupled with crude reaction mixture screening (direct-to-biology). This effort yielded the most potent small-molecule DsbA inhibitors reported to date and exemplifies a productive strategy for exploiting a cryptic pocket for drug development.

PubMed: 41789772
DOI: 10.1021/acs.jmedchem.5c03004

実験手法

X-RAY DIFFRACTION (1.61 Å)