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| | <StructureSection load='6vus' size='340' side='right'caption='[[6vus]], [[Resolution|resolution]] 2.28Å' scene=''> | | <StructureSection load='6vus' size='340' side='right'caption='[[6vus]], [[Resolution|resolution]] 2.28Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6vus]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Myctu Myctu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6VUS OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6VUS FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6vus]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Myctu Myctu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6VUS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VUS FirstGlance]. <br> |
| | </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=RNV:2-[(4-amino-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-2-yl)sulfanyl]-N-[2-(diethylamino)ethyl]acetamide'>RNV</scene></td></tr> | | </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=RNV:2-[(4-amino-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-2-yl)sulfanyl]-N-[2-(diethylamino)ethyl]acetamide'>RNV</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">eis, Rv2416c, MTCY253.04 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</td></tr> | + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">eis, Rv2416c, MTCY253.04 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6vus FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vus OCA], [http://pdbe.org/6vus PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6vus RCSB], [http://www.ebi.ac.uk/pdbsum/6vus PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6vus ProSAT]</span></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=6vus FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vus OCA], [https://pdbe.org/6vus PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vus RCSB], [https://www.ebi.ac.uk/pdbsum/6vus PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vus ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [[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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Structural highlights
Function
[EIS_MYCTU] May participate in pathogenesis, possibly by enhancing survival of the bacteria in host macrophages during infection.[1]
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[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wei J, Dahl JL, Moulder JW, Roberts EA, O'Gaora P, Young DB, Friedman RL. Identification of a Mycobacterium tuberculosis gene that enhances mycobacterial survival in macrophages. J Bacteriol. 2000 Jan;182(2):377-84. PMID:10629183
- ↑ 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. Structure-Guided Optimization of Inhibitors of Acetyltransferase Eis from Mycobacterium tuberculosis. ACS Chem Biol. 2020 Jun 19;15(6):1581-1594. doi: 10.1021/acschembio.0c00184. Epub, 2020 May 18. PMID:32421305 doi:http://dx.doi.org/10.1021/acschembio.0c00184
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