8qf2 | pdb_00008qf2

Beta-L-Arabinofurano-cyclitol Aziridines are Cysteine-directed Broad-spectrum Inhibitors and Activity-based Probes for Retaining Beta-L-arabinofuranosidases

spinqualitylabelsall models 8qf2, resolution 2.35Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8qf2 is a 1 chain structure with sequence from Bifidobacterium longum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.35Å Ligands: UI5, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function HYBA1_BIFL2 Beta-L-arabinofuranosidase that removes the beta-L-arabinofuranose residue from the non-reducing end of various substrates, including beta-L-arabinofuranosyl-hydroxyproline (Ara-Hyp), Ara-beta-1,2-Ara-beta-Hyp (Ara(2)-Hyp), Ara-beta-1,2-Ara-beta-1,2-Ara-beta-Hyp (Ara(3)-Hyp), and beta-L-arabinofuranosyl-(1->2)-1-O-methyl-beta-L-arabinofuranose. In the presence of 1-alkanols, shows transglycosylation activity, retaining the anomeric configuration of the arabinofuranose residue. Publication Abstract from PubMed GH127 and GH146 microorganismal retaining beta-l-arabinofuranosidases, expressed by human gut microbiomes, feature an atypical catalytic domain and an unusual mechanism of action. We recently reported that both Bacteroides thetaiotaomicron BtGH146 and Bifidobacterium longum HypBA1 are inhibited by beta-l-arabinofuranosyl cyclophellitol epoxide, supporting the action of a zinc-coordinated cysteine as a catalytic nucleophile, where in most retaining GH families, an aspartate or glutamate is employed. This work presents a panel of beta-l-arabinofuranosyl cyclophellitol epoxides and aziridines as mechanism-based BtGH146/HypBA1 inhibitors and activity-based probes. The beta-l-arabinofuranosyl cyclophellitol aziridines both inhibit and label beta-l-arabinofuranosidase efficiently (however with different activities), whereas the epoxide-derived probes favor BtGH146 over HypBA1. These findings are accompanied by X-ray structural analysis of the unmodified beta-l-arabinofuranosyl cyclophellitol aziridine in complex with both isozymes, which were shown to react by nucleophilic opening of the aziridine, at the pseudoanomeric carbon, by the active site cysteine nucleophile to form a stable thioether bond. Altogether, our activity-based probes may serve as chemical tools for the detection and identification of low-abundance beta-l-arabinofuranosidases in complex biological samples. beta-l-Arabinofurano-cyclitol Aziridines Are Covalent Broad-Spectrum Inhibitors and Activity-Based Probes for Retaining beta-l-Arabinofuranosidases.,Borlandelli V, Offen W, Moroz O, Nin-Hill A, McGregor N, Binkhorst L, Ishiwata A, Armstrong Z, Artola M, Rovira C, Davies GJ, Overkleeft HS ACS Chem Biol. 2023 Dec 15;18(12):2564-2573. doi: 10.1021/acschembio.3c00558. , Epub 2023 Dec 5. PMID:38051515 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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