4zil

Crystal structure of Rv2466c and oxidoreductase from Mycobacterium tuberculosis in its reduced state

spinqualitylabelsall models 4zil, resolution 1.51Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4zil is a 2 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.507Å Ligands: MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function TRLR_MYCTU In vitro, the reduced form of Rv2466c catalyzes the reduction and activation of TP053, which is a thienopyrimidine derivative drug that can kill both replicating and non-replicating M.tuberculosis. Publication Abstract from PubMed Rv2466c is a key oxidoreductase that mediates the reductive activation of TP053, a thienopyrimidine derivative that kills replicating and non-replicating Mycobacterium tuberculosis, but whose mode of action remains enigmatic. Rv2466c is a homodimer in which each subunit displays a modular architecture comprising a canonical thioredoxin fold with a Cys19-Pro20-Trp21-Cys22 motif, and an insertion consisting of a four alpha-helical bundle and a short alpha-helical hairpin. Strong evidence is provided for dramatic conformational changes during the Rv2466c redox cycle, which are essential for TP053 activity. Strikingly, a new crystal structure of the reduced form of Rv2466c revealed the binding of a C-terminal extension in alpha-helical conformation to a pocket next to the active site cysteine pair at the interface between the thioredoxin domain and the helical insertion domain. The ab initio low-resolution envelopes obtained from small angle X-ray scattering showed that the fully reduced form of Rv2466c adopts a 'closed' compact conformation in solution, similar to that observed in the crystal structure. In contrast, the oxidized form of Rv2466c displays an 'open' conformation, where tertiary structural changes in the alpha-helical subdomain suffice to account for the observed conformational transitions. Altogether our structural, biochemical and biophysical data strongly support a model in which the formation of the catalytic disulfide bond upon TP053 reduction triggers local structural changes that open the substrate binding site of Rv2466c allowing the release of the activated, reduced form of TP053. Our studies suggest that similar structural changes might have a functional role in other members of the thioredoxin-fold superfamily. The redox state regulates the conformation of Rv2466c to activate the antitubercular prodrug TP053.,Albesa-Jove D, Comino N, Tersa M, Mohorko E, Urresti S, Dainese E, Chiarelli LR, Pasca MR, Manganelli R, Makarov V, Riccardi G, Svergun DI, Glockshuber R, Guerin ME J Biol Chem. 2015 Nov 6. pii: jbc.M115.677039. PMID:26546681 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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