6vux: Difference between revisions
New page: '''Unreleased structure''' The entry 6vux is ON HOLD Authors: Description: Category: Unreleased Structures |
No edit summary |
||
| (5 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
The | ==Crystal structure of Eis from Mycobacterium tuberculosis in complex with inhibitor SGT388== | ||
<StructureSection load='6vux' size='340' side='right'caption='[[6vux]], [[Resolution|resolution]] 1.97Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6vux]] 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=6VUX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VUX 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]] 1.97Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=H66:2-{[(7S)-4-amino-7-ethyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-2-yl]sulfanyl}-N-[2-(piperidin-1-yl)ethyl]acetamide'>H66</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6vux FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vux OCA], [https://pdbe.org/6vux PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vux RCSB], [https://www.ebi.ac.uk/pdbsum/6vux PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vux 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 == | |||
The enhanced intracellular survival (Eis) protein of Mycobacterium tuberculosis (Mtb) is a versatile acetyltransferase that multiacetylates aminoglycoside antibiotics abolishing their binding to the bacterial ribosome. When overexpressed as a result of promoter mutations, Eis causes drug resistance. In an attempt to overcome the Eis-mediated kanamycin resistance of Mtb, we designed and optimized structurally unique thieno[2,3-d]pyrimidine Eis inhibitors toward effective kanamycin adjuvant combination therapy. We obtained 12 crystal structures of enzyme-inhibitor complexes, which guided our rational structure-based design of 72 thieno[2,3-d]pyrimidine analogues divided into three families. We evaluated the potency of these inhibitors in vitro as well as their ability to restore the activity of kanamycin in a resistant strain of Mtb, in which Eis was upregulated. Furthermore, we evaluated the metabolic stability of 11 compounds in vitro. This study showcases how structural information can guide Eis inhibitor design. | |||
Structure-Guided Optimization of Inhibitors of Acetyltransferase Eis from Mycobacterium tuberculosis.,Punetha A, Ngo HX, Holbrook SYL, Green KD, Willby MJ, Bonnett SA, Krieger K, Dennis EK, Posey JE, Parish T, Tsodikov OV, Garneau-Tsodikova S ACS Chem Biol. 2020 Jun 19;15(6):1581-1594. doi: 10.1021/acschembio.0c00184. Epub, 2020 May 18. PMID:32421305<ref>PMID:32421305</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6vux" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Mycobacterium tuberculosis H37Rv]] | |||
[[Category: Garneau-Tsodikova S]] | |||
[[Category: Hou C]] | |||
[[Category: Ngo HX]] | |||
[[Category: Punetha A]] | |||
[[Category: Tsodikov OV]] | |||
Latest revision as of 11:20, 11 October 2023
Crystal structure of Eis from Mycobacterium tuberculosis in complex with inhibitor SGT388Crystal structure of Eis from Mycobacterium tuberculosis in complex with inhibitor SGT388
Structural highlights
FunctionEIS_MYCTU May participate in pathogenesis, possibly by enhancing survival of the bacteria in host macrophages during infection.[1] Publication Abstract from PubMedThe enhanced intracellular survival (Eis) protein of Mycobacterium tuberculosis (Mtb) is a versatile acetyltransferase that multiacetylates aminoglycoside antibiotics abolishing their binding to the bacterial ribosome. When overexpressed as a result of promoter mutations, Eis causes drug resistance. In an attempt to overcome the Eis-mediated kanamycin resistance of Mtb, we designed and optimized structurally unique thieno[2,3-d]pyrimidine Eis inhibitors toward effective kanamycin adjuvant combination therapy. We obtained 12 crystal structures of enzyme-inhibitor complexes, which guided our rational structure-based design of 72 thieno[2,3-d]pyrimidine analogues divided into three families. We evaluated the potency of these inhibitors in vitro as well as their ability to restore the activity of kanamycin in a resistant strain of Mtb, in which Eis was upregulated. Furthermore, we evaluated the metabolic stability of 11 compounds in vitro. This study showcases how structural information can guide Eis inhibitor design. Structure-Guided Optimization of Inhibitors of Acetyltransferase Eis from Mycobacterium tuberculosis.,Punetha A, Ngo HX, Holbrook SYL, Green KD, Willby MJ, Bonnett SA, Krieger K, Dennis EK, Posey JE, Parish T, Tsodikov OV, Garneau-Tsodikova S ACS Chem Biol. 2020 Jun 19;15(6):1581-1594. doi: 10.1021/acschembio.0c00184. Epub, 2020 May 18. PMID:32421305[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||||