8ogs

PanDDA analysis group deposition -- CdaA in complex with fragment F2X-Entry B08

spinqualitylabelsall models 8ogs, resolution 1.25Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8ogs is a 2 chain structure with sequence from Bacillus subtilis subsp. subtilis str. 168. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.25Å Ligands: MG, T9S Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CDAA_BACSU One of 3 paralogous diadenylate cyclases (DAC) in this bacteria, catalyzing the condensation of 2 ATP molecules into cyclic di-AMP (c-di-AMP) (Probable). Upon expression in E.coli leads to c-di-AMP synthesis (PubMed:23192352). Probably the main producer of c-di-AMP for the cell; is probably implicated in control of peptidoglycan synthesis (PubMed:22211522, PubMed:23192352, PubMed:26240071). In B.subtilis c-di-AMP is a second messenger that mediates growth, DNA repair and cell wall homeostasis; it is toxic when present in excess (PubMed:26240071). Publication Abstract from PubMed Crystallographic fragment screening has become a pivotal technique in structure-based drug design, particularly for bacterial targets with a crucial role in infectious disease mechanisms. The enzyme CdaA, which synthesizes an essential second messenger cyclic di-AMP (c-di-AMP) in many pathogenic bacteria, has emerged as a promising candidate for the development of novel antibiotics. To identify crystals suitable for fragment screening, CdaA enzymes from Streptococcus pneumoniae, Bacillus subtilis and Enterococcus faecium were purified and crystallized. Crystals of B. subtilis CdaA, which diffracted to the highest resolution of 1.1 A, were used to perform the screening of 96 fragments, yielding data sets with resolutions spanning from 1.08 to 1.87 A. A total of 24 structural hits across eight different sites were identified. Four fragments bind to regions that are highly conserved among pathogenic bacteria, specifically the active site (three fragments) and the dimerization interface (one fragment). The coordinates of the three active-site fragments were used to perform an in silico drug-repurposing screen using the OpenEye suite and the DrugBank database. This screen identified tenofovir, an approved drug, that is predicted to interact with the ATP-binding region of CdaA. Its inhibitory potential against pathogenic E. faecium CdaA has been confirmed by ITC measurements. These findings not only demonstrate the feasibility of this approach for identifying lead compounds for the design of novel antibacterial agents, but also pave the way for further fragment-based lead-optimization efforts targeting CdaA. Crystallographic fragment screen of the c-di-AMP-synthesizing enzyme CdaA from Bacillus subtilis.,Garbers T, Neumann P, Wollenhaupt J, Dickmanns A, Weiss MS, Ficner R Acta Crystallogr F Struct Biol Commun. 2024 Sep 1;80(Pt 9):200-209. doi: , 10.1107/S2053230X24007039. Epub 2024 Aug 23. PMID:39177700 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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