9pre
Crystal structure of oxidised E.coli DsbA in complex with propiolic acid
Structural highlights
FunctionDSBA_ECOLI Required for disulfide bond formation in some periplasmic proteins such as PhoA or OmpA. Acts by transferring its disulfide bond to other proteins and is reduced in the process. DsbA is reoxidized by DsbB. Required for pilus biogenesis. PhoP-regulated transcription is redox-sensitive, being activated when the periplasm becomes more reducing (deletion of dsbA/dsbB, treatment with dithiothreitol). MgrB acts between DsbA/DsbB and PhoP/PhoQ in this pathway.[1] [2] Publication Abstract from PubMedAntibacterial 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 Escherichia coli 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 EcDsbA inhibitors reported to date and exemplifies a productive strategy for exploiting a cryptic pocket for drug development. Exploiting a Cryptic Pocket in DsbA through Structure-Guided Parallel Synthesis and Direct-to-Biology Screening.,Tasdan Y, Balaji GR, Davidson J, Akhtar N, Ilyichova O, Guetzoyan LJ, Chandrashekaran IR, Alwan W, Cobb H, Gunzburg MJ, Hasanzada A, Roughley SD, Murray JB, Thai VC, Cliff T, Kahler CM, Mohanty B, Capuano B, Doak BC, Scanlon MJ J Med Chem. 2026 Mar 6. doi: 10.1021/acs.jmedchem.5c03004. PMID:41789772[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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