Amyloid-b peptide (Ab)o ligomers are pathogenic species of amyloid aggregates in Alzheimersd isease.L ike certain protein toxins,A b oligomers permeabilizec ellular membranes,p resumably through ap ore formation mechanism. Owing to their structural and stoichiometric heterogeneity,the structure of these pores remains to be characterized. We studied af unctional Ab42-pore equivalent, created by fusing Ab42 to the oligomerizing,s oluble domain of the ahemolysin (aHL) toxin. Our data reveal Ab42-aHL oligomers to share major structural, functional, and biological properties with wild-type Ab42-pores.Single-particle cryo-EM analysis of Ab42-aHL oligomers (with an overall 3.3 resolution) reveals the Ab42-pore region to be intrinsically flexible.T he Ab42-aHL oligomers will allow many of the features of the wild-type amyloid oligomers to be studied that cannot be otherwise,a nd mayb eah ighly specific antigen for the development of immuno-base diagnostics and therapies.

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Angucyclines are a structurally diverse class of actinobacterial natural products defined by their varied polycyclic ring systems, which display a wide range of biological activities. We recently discovered lugdunomycin ( 1 ), a highly rearranged polyketide antibiotic derived from the angucycline backbone that is synthesized via several yet unexplained enzymatic reactions. Here, we show via in vivo , in vitro , and structural analysis that the promiscuous reductase LugOII catalyzes both a C6 and an unprecedented C1 ketoreduction. This then sets the stage for the subsequent C-ring cleavage that is key to the rearranged scaffolds of 1 . The 1.1 Å structures of LugOII in complex with either ligand 8- O -Methylrabelomycin ( 4 ) or 8- O -Methyltetrangomycin ( 5 ) and of apoenzyme were resolved, which revealed a canonical Rossman fold and a remarkable conformational change during substrate capture and release. Mutational analysis uncovered key residues for substrate access, position, and catalysis as well as specific determinants that control its dual functionality. The insights obtained in this work hold promise for the discovery and engineering of other promiscuous reductases that may be harnessed for the generation of novel biocatalysts for chemoenzymatic applications.