2WDW

The Native Crystal Structure of the Primary Hexose Oxidase (Dbv29) in Antibiotic A40926 Biosynthesis

Summary for 2WDW

• Entry DOI: 10.2210/pdb2wdw/pdb
• Related: 2WDX
• Descriptor: PUTATIVE HEXOSE OXIDASE, FLAVIN-ADENINE DINUCLEOTIDE (3 entities in total)
• Functional Keywords: fad, flavoprotein, hexose oxidase, oxidoreductase
• Biological source: NONOMURAEA SP. ATCC 39727
• Total number of polymer chains: 2
• Total formula weight: 115689.12

Authors

Liu, Y.-C.,Li, Y.-S.,Lyu, S.-Y.,Chen, Y.-H.,Chan, H.-C.,Huang, C.-J.,Huang, Y.-T.,Chen, G.-H.,Chou, C.-C.,Tsai, M.-D.,Li, T.-L. (deposition date: 2009-03-27, release date: 2010-04-07, Last modification date: 2024-10-23)

Primary citation

Liu, Y.-C.,Li, Y.-S.,Lyu, S.-Y.,Hsu, L.-J.,Chen, Y.-H.,Huang, Y.-T.,Chan, H.-C.,Huang, C.-J.,Chen, G.-H.,Chou, C.-C.,Tsai, M.-D.,Li, T.-L.
Interception of Teicoplanin Oxidation Intermediates Yields New Antimicrobial Scaffolds
Nat.Chem.Biol., 7:304-, 2011

PubMed Abstract: In the search for new efficacious antibiotics, biosynthetic engineering offers attractive opportunities to introduce minor alterations to antibiotic structures that may overcome resistance. Dbv29, a flavin-containing oxidase, catalyzes the four-electron oxidation of a vancomycin-like glycopeptide to yield A40926. Structural and biochemical examination of Dbv29 now provides insights into residues that govern flavinylation and activity, protein conformation and reaction mechanism. In particular, the serendipitous discovery of a reaction intermediate in the crystal structure led us to identify an unexpected opportunity to intercept the normal enzyme mechanism at two different points to create new teicoplanin analogs. Using this method, we synthesized families of antibiotic analogs with amidated and aminated lipid chains, some of which showed marked potency and efficacy against multidrug resistant pathogens. This method offers a new strategy for the development of chemical diversity to combat antibacterial resistance.

PubMed: 21478878
DOI: 10.1038/NCHEMBIO.556

Experimental method

X-RAY DIFFRACTION (3.21 Å)