View source for 9dtv


==Structure of D141A mutant of M.tuberculosis MenD (SEPHCHC Synthase)==
<StructureSection load='9dtv' size='340' side='right'caption='[[9dtv]], [[Resolution|resolution]] 2.42&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9dtv]] is a 4 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=9DTV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9DTV 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]] 2.42&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DNA:1,4-DIHYDROXY-2-NAPHTHOIC+ACID'>DNA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=TPP:THIAMINE+DIPHOSPHATE'>TPP</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=9dtv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9dtv OCA], [https://pdbe.org/9dtv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9dtv RCSB], [https://www.ebi.ac.uk/pdbsum/9dtv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9dtv ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/MEND_MYCTU MEND_MYCTU] Catalyzes the thiamine diphosphate-dependent decarboxylation of 2-oxoglutarate and the subsequent addition of the resulting succinic semialdehyde-thiamine pyrophosphate anion to isochorismate to yield 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexene-1-carboxylate (SEPHCHC).
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== Publication Abstract from PubMed ==
Redox-active molecules play critical roles in various biological functions, including cellular respiration. In bacterial electron transport chains, menaquinones serve as key electron carriers. The first committed enzyme in the menaquinone biosynthesis pathway of Mycobacterium tuberculosis (Mtb), MenD, is allosterically inhibited by 1,4-dihydroxy-2-naphthoic acid (DHNA), the first redox-active metabolite in the pathway. Structural asymmetries in Mtb-MenD suggest that this enzyme operates via a half-of-sites mechanism for catalysis. Here, we investigate the interplay between its catalytic and allosteric mechanisms. Using molecular dynamics (MD) simulations, mutagenesis, kinetic and binding assays, and structural analyses, we identified and characterised mutants of two residues, D141 and D306, involved in stabilising asymmetric conformations associated with allostery. These mutations had complex effects on Mtb-MenD's reaction kinetics, with the D306 mutants showing an apparent reversal of the allosteric response to DHNA. Our findings indicate that asymmetric active site conformations may facilitate optimal binding of cofactors and substrates, while the transition between alternating active site conformations is essential for the catalytic cycle. DHNA binding stabilises asymmetry in the tetramer, likely promoting the binding of cofactors, substrates, or reaction intermediates. However, DHNA interferes with the transition between alternating conformations, ultimately impairing turnover and catalytic cycling in Mtb-MenD.

Apparent Reversal of Allosteric Response in Mycobacterium tuberculosis MenD Reveals Links to Half-of-Sites Reactivity.,Ho NAT, Given FM, Stanborough T, Klein M, Allison TM, Bulloch EMM, Jiao W, Johnston JM Chembiochem. 2025 Feb 13:e202400943. doi: 10.1002/cbic.202400943. PMID:39945237<ref>PMID:39945237</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9dtv" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Mycobacterium tuberculosis H37Rv]]
[[Category: Allison TM]]
[[Category: Bulloch EMM]]
[[Category: Given FM]]
[[Category: Ho NAT]]
[[Category: Jiao W]]
[[Category: Johnston JM]]