6pml

Crystal Structure of EcDsbA in complex benzyl ether 23

spinqualitylabelsall models 6pml, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6pml is a 2 chain structure with sequence from Ecoli. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CU, OR4, PEG Gene: dsbA, dsf, ppfA, b3860, JW3832 (ECOLI) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [DSBA_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. Publication Abstract from PubMed A fragment-based drug discovery approach was taken to target the thiol-disulfide oxidoreductase enzyme DsbA from Escherichia coli (EcDsbA). This enzyme is critical for the correct folding of virulence factors in many pathogenic Gram-negative bacteria, and small molecule inhibitors can potentially be developed as anti-virulence compounds. Biophysical screening of a library of fragments identified several classes of fragments with affinity to EcDsbA. One hit with high mM affinity, 2-(6-bromobenzofuran-3-yl)acetic acid (6), was chemically elaborated at several positions around the scaffold. X-ray crystal structures of the elaborated analogues showed binding in the hydrophobic binding groove adjacent to the catalytic disulfide bond of EcDsbA. Binding affinity was calculated based on NMR studies and compounds 25 and 28 were identified as the highest affinity binders with dissociation constants (KD) of 326 +/- 25 and 341 +/- 57 microM respectively. This work suggests the potential to develop benzofuran fragments into a novel class of EcDsbA inhibitors. The Fragment-Based Development of a Benzofuran Hit as a New Class of Escherichia coli DsbA Inhibitors.,Duncan LF, Wang G, Ilyichova OV, Scanlon MJ, Heras B, Abbott BM Molecules. 2019 Oct 18;24(20). pii: molecules24203756. doi:, 10.3390/molecules24203756. PMID:31635355 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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