9EGR

Crystal structure of oxidised E.coli DsbA in complex with allene

This is a non-PDB format compatible entry.

Summary for 9EGR

• Entry DOI: 10.2210/pdb9egr/pdb
• Descriptor: Thiol:disulfide interchange protein DsbA, methyl 4-{3-[(5-methyl-1,2-oxazole-3-carbonyl)amino]phenyl}butanoate (3 entities in total)
• Functional Keywords: oxidoreductase, oxidoreductase inhibitor
• Biological source: Escherichia coli
• Total number of polymer chains: 2
• Total formula weight: 46561.30

Authors

Balaji, G.R.,Tasdan, Y.,Ilyichova, O.V.,Akhtar, N.,Scanlon, M.J. (deposition date: 2024-11-21, release date: 2024-12-11, Last modification date: 2025-06-25)

Primary citation

Tasdan, Y.,Balaji, G.R.,Akhtar, N.,Ilyichova, O.,Cunliffe, T.,Heras, B.,Strat, L.L.,Murray, J.,Capuano, B.,Scanlon, M.J.,Doak, B.C.
Identification of an Allene Warhead That Selectively Targets a Histidine Residue in the Escherichia coli Oxidoreductase Enzyme DsbA.
Acs Med.Chem.Lett., 16:625-630, 2025

PubMed Abstract: Small molecules that covalently modify proteins typically contain an electrophile that selectively reacts with nucleophilic residues in a protein target, such as cysteine, serine, and threonine. Targeting other amino acids is an emerging strategy in covalent probe design. This study reports the discovery and characterization of the covalent reaction between a novel allene warhead and a histidine residue in the active site of the bacterial thiol-disulfide oxidoreductase enzyme DsbA (DsbA). Allenes have not been widely reported for their use as covalent warheads. The interaction was characterized by X-ray crystallography, nuclear magnetic resonance spectroscopy, and mass spectrometry. This analysis provided insights into the structure, reaction rate, and selectivity of the allene. Investigation of the reactivity with nucleophilic amino acids revealed that the reaction with the allene warhead shows some specificity for the histidine in the active site of DsbA. Thus, the allene represents a novel histidine-modifying warhead.

PubMed: 40236539
DOI: 10.1021/acsmedchemlett.5c00016

Experimental method

X-RAY DIFFRACTION (1.62 Å)