6tj8

Escherichia coli transketolase in complex with cofactor analog 2'-methoxythiamine diphosphate

spinqualitylabelsall models 6tj8, resolution 0.92Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6tj8 is a 2 chain structure with sequence from Escherichia coli K-12. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 0.921Å Ligands: CA, EDO, NDQ Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function TKT1_ECOLI Catalyzes the reversible transfer of a two-carbon ketol group from sedoheptulose-7-phosphate to glyceraldehyde-3-phosphate, producing xylulose-5-phosphate and ribose-5-phosphate. Catalyzes the transfer of a two-carbon ketol group from a ketose donor to an aldose acceptor, via a covalent intermediate with the cofactor thiamine pyrophosphate. Publication Abstract from PubMed The natural antivitamin 2'-methoxy-thiamine (MTh) is implicated in the suppression of microbial growth. However, its mode of action and enzyme-selective inhibition mechanism have remained elusive. Intriguingly, MTh inhibits some thiamine diphosphate (ThDP) enzymes, while being coenzymatically active in others. Here we report the strong inhibition of Escherichia coli transketolase activity by MTh and unravel its mode of action and the structural basis thereof. The unique 2'-methoxy group of MTh diphosphate (MThDP) clashes with a canonical glutamate required for cofactor activation in ThDP-dependent enzymes. This glutamate is forced into a stable, anticatalytic low-barrier hydrogen bond with a neighboring glutamate, disrupting cofactor activation. Molecular dynamics simulations of transketolases and other ThDP enzymes identify active-site flexibility and the topology of the cofactor-binding locale as key determinants for enzyme-selective inhibition. Human enzymes either retain enzymatic activity with MThDP or preferentially bind authentic ThDP over MThDP, while core bacterial metabolic enzymes are inhibited, demonstrating therapeutic potential. Structural basis for antibiotic action of the B1 antivitamin 2'-methoxy-thiamine.,Rabe von Pappenheim F, Aldeghi M, Shome B, Begley T, de Groot BL, Tittmann K Nat Chem Biol. 2020 Aug 24. pii: 10.1038/s41589-020-0628-4. doi:, 10.1038/s41589-020-0628-4. PMID:32839604 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Transketolase 3D structures

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