8f4a: Difference between revisions
New page: '''Unreleased structure''' The entry 8f4a is ON HOLD Authors: Description: Category: Unreleased Structures |
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The | ==Crystal structure of acetyltransferase Eis from M. tuberculosis in complex with chlorhexidine== | ||
<StructureSection load='8f4a' size='340' side='right'caption='[[8f4a]], [[Resolution|resolution]] 2.41Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8f4a]] is a 1 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=8F4A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8F4A 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]] 2.41Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=XC9:1-[6-[azanylidene-[[azanylidene-[[(4-chlorophenyl)amino]methyl]-$l^{4}-azanyl]methyl]-$l^{4}-azanyl]hexyl]-3-[~{N}-(4-chlorophenyl)carbamimidoyl]guanidine'>XC9</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=8f4a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8f4a OCA], [https://pdbe.org/8f4a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8f4a RCSB], [https://www.ebi.ac.uk/pdbsum/8f4a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8f4a ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/EIS_MYCTU EIS_MYCTU] May participate in pathogenesis, possibly by enhancing survival of the bacteria in host macrophages during infection.<ref>PMID:10629183</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Over one and a half million people die of tuberculosis (TB) each year. Multidrug-resistant TB infections are especially dangerous, and new drugs are needed to combat them. The high cost and complexity of drug development make repositioning of drugs that are already in clinical use for other indications a potentially time- and money-saving avenue. In this study, we identified among existing drugs five compounds: azelastine, venlafaxine, chloroquine, mefloquine, and proguanil as inhibitors of acetyltransferase Eis from Mycobacterium tuberculosis, a causative agent of TB. Eis upregulation is a cause of clinically relevant resistance of TB to kanamycin, which is inactivated by Eis-catalyzed acetylation. Crystal structures of these drugs as well as chlorhexidine in complexes with Eis showed that these inhibitors were bound in the aminoglycoside binding cavity, consistent with their established modes of inhibition with respect to kanamycin. Among three additionally synthesized compounds, a proguanil analogue, designed based on the crystal structure of the Eis-proguanil complex, was 3-fold more potent than proguanil. The crystal structures of these compounds in complexes with Eis explained their inhibitory potencies. These initial efforts in rational drug repositioning can serve as a starting point in further development of Eis inhibitors. | |||
Discovery and Mechanistic Analysis of Structurally Diverse Inhibitors of Acetyltransferase Eis among FDA-Approved Drugs.,Pang AH, Green KD, Punetha A, Thamban Chandrika N, Howard KC, Garneau-Tsodikova S, Tsodikov OV Biochemistry. 2023 Jan 19. doi: 10.1021/acs.biochem.2c00658. PMID:36657084<ref>PMID:36657084</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 8f4a" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Mycobacterium tuberculosis H37Rv]] | |||
[[Category: Garneau-Tsodikova S]] | |||
[[Category: Pang AH]] | |||
[[Category: Punetha A]] | |||
[[Category: Tsodikov OV]] | |||
Latest revision as of 13:29, 25 October 2023
Crystal structure of acetyltransferase Eis from M. tuberculosis in complex with chlorhexidineCrystal structure of acetyltransferase Eis from M. tuberculosis in complex with chlorhexidine
Structural highlights
FunctionEIS_MYCTU May participate in pathogenesis, possibly by enhancing survival of the bacteria in host macrophages during infection.[1] Publication Abstract from PubMedOver one and a half million people die of tuberculosis (TB) each year. Multidrug-resistant TB infections are especially dangerous, and new drugs are needed to combat them. The high cost and complexity of drug development make repositioning of drugs that are already in clinical use for other indications a potentially time- and money-saving avenue. In this study, we identified among existing drugs five compounds: azelastine, venlafaxine, chloroquine, mefloquine, and proguanil as inhibitors of acetyltransferase Eis from Mycobacterium tuberculosis, a causative agent of TB. Eis upregulation is a cause of clinically relevant resistance of TB to kanamycin, which is inactivated by Eis-catalyzed acetylation. Crystal structures of these drugs as well as chlorhexidine in complexes with Eis showed that these inhibitors were bound in the aminoglycoside binding cavity, consistent with their established modes of inhibition with respect to kanamycin. Among three additionally synthesized compounds, a proguanil analogue, designed based on the crystal structure of the Eis-proguanil complex, was 3-fold more potent than proguanil. The crystal structures of these compounds in complexes with Eis explained their inhibitory potencies. These initial efforts in rational drug repositioning can serve as a starting point in further development of Eis inhibitors. Discovery and Mechanistic Analysis of Structurally Diverse Inhibitors of Acetyltransferase Eis among FDA-Approved Drugs.,Pang AH, Green KD, Punetha A, Thamban Chandrika N, Howard KC, Garneau-Tsodikova S, Tsodikov OV Biochemistry. 2023 Jan 19. doi: 10.1021/acs.biochem.2c00658. PMID:36657084[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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