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==Structure of Mtb Lpd bound to SL827== | |||
=== | <StructureSection load='4m52' size='340' side='right' caption='[[4m52]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4m52]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4M52 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4M52 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=M52:N~2~-[(2-AMINO-5-BROMOPYRIDIN-3-YL)SULFONYL]-N-(4-METHOXYPHENYL)-N~2~-METHYLGLYCINAMIDE'>M52</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3ii4|3ii4]], [[2a8x|2a8x]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">lpd, LPD RV0462, lpdC, MT0478, MTV038.06, Rv0462 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dihydrolipoyl_dehydrogenase Dihydrolipoyl dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.8.1.4 1.8.1.4] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4m52 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4m52 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4m52 RCSB], [http://www.ebi.ac.uk/pdbsum/4m52 PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Tuberculosis remains a global health emergency that calls for treatment regimens directed at new targets. Here we explored lipoamide dehydrogenase (Lpd), a metabolic and detoxifying enzyme in Mycobacterium tuberculosis (Mtb) whose deletion drastically impairs Mtb's ability to establish infection in the mouse. Upon screening more than 1.6 million compounds, we identified N-methylpyridine 3-sulfonamides as potent and species-selective inhibitors of Mtb Lpd affording >1000-fold selectivity versus the human homologue. The sulfonamides demonstrated low nanomolar affinity and bound at the lipoamide channel in an Lpd-inhibitor cocrystal. Their selectivity could be attributed, at least partially, to hydrogen bonding of the sulfonamide amide oxygen with the species variant Arg93 in the lipoamide channel. Although potent and selective, the sulfonamides did not enter mycobacteria, as determined by their inability to accumulate in Mtb to effective levels or to produce changes in intracellular metabolites. This work demonstrates that high potency and selectivity can be achieved at the lipoamide-binding site of Mtb Lpd, a site different from the NAD+/NADH pocket targeted by previously reported species-selective triazaspirodimethoxybenzoyl inhibitors. | |||
Lipoamide Channel-Binding Sulfonamides Selectively Inhibit Mycobacterial Lipoamide Dehydrogenase.,Bryk R, Arango N, Maksymiuk C, Balakrishnan A, Wu YT, Wong CH, Masquelin T, Hipskind P, Lima CD, Nathan C Biochemistry. 2013 Nov 26. PMID:24251446<ref>PMID:24251446</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== | ==See Also== | ||
*[[Dihydrolipoamide dehydrogenase|Dihydrolipoamide dehydrogenase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Dihydrolipoyl dehydrogenase]] | [[Category: Dihydrolipoyl dehydrogenase]] | ||
[[Category: Lima, C D | [[Category: Lima, C D]] | ||
[[Category: Flavoprotein]] | [[Category: Flavoprotein]] | ||
[[Category: Glycolysis]] | [[Category: Glycolysis]] | ||
[[Category: Oxidoreductase]] | [[Category: Oxidoreductase]] | ||
[[Category: Redox-active center]] | [[Category: Redox-active center]] | ||
Revision as of 20:58, 21 December 2014
Structure of Mtb Lpd bound to SL827Structure of Mtb Lpd bound to SL827
Structural highlights
Publication Abstract from PubMedTuberculosis remains a global health emergency that calls for treatment regimens directed at new targets. Here we explored lipoamide dehydrogenase (Lpd), a metabolic and detoxifying enzyme in Mycobacterium tuberculosis (Mtb) whose deletion drastically impairs Mtb's ability to establish infection in the mouse. Upon screening more than 1.6 million compounds, we identified N-methylpyridine 3-sulfonamides as potent and species-selective inhibitors of Mtb Lpd affording >1000-fold selectivity versus the human homologue. The sulfonamides demonstrated low nanomolar affinity and bound at the lipoamide channel in an Lpd-inhibitor cocrystal. Their selectivity could be attributed, at least partially, to hydrogen bonding of the sulfonamide amide oxygen with the species variant Arg93 in the lipoamide channel. Although potent and selective, the sulfonamides did not enter mycobacteria, as determined by their inability to accumulate in Mtb to effective levels or to produce changes in intracellular metabolites. This work demonstrates that high potency and selectivity can be achieved at the lipoamide-binding site of Mtb Lpd, a site different from the NAD+/NADH pocket targeted by previously reported species-selective triazaspirodimethoxybenzoyl inhibitors. Lipoamide Channel-Binding Sulfonamides Selectively Inhibit Mycobacterial Lipoamide Dehydrogenase.,Bryk R, Arango N, Maksymiuk C, Balakrishnan A, Wu YT, Wong CH, Masquelin T, Hipskind P, Lima CD, Nathan C Biochemistry. 2013 Nov 26. PMID:24251446[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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