View source for 4zil


==Crystal structure of Rv2466c and oxidoreductase from Mycobacterium tuberculosis in its reduced state==
<StructureSection load='4zil' size='340' side='right'caption='[[4zil]], [[Resolution|resolution]] 1.51&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4zil]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ZIL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZIL FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.507&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4zil FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zil OCA], [https://pdbe.org/4zil PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zil RCSB], [https://www.ebi.ac.uk/pdbsum/4zil PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zil ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/TRLR_MYCTU 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.<ref>PMID:24877756</ref> 
<div style="background-color:#fffaf0;">
== 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<ref>PMID:26546681</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4zil" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Mycobacterium tuberculosis H37Rv]]
[[Category: Albesa-Jove D]]
[[Category: Comino N]]
[[Category: Guerin ME]]
[[Category: Tersa M]]
[[Category: Urresti S]]