6vv3: Difference between revisions

Latest revision as of 08:20, 11 October 2023

Crystal structure of Eis from Mycobacterium tuberculosis in complex with inhibitor SGT1358

Structural highlights

6vv3 is a 1 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.4Å
Ligands:	CL, DMS, PEG, RM7, SO4
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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:https://dx.doi.org/10.1021/acschembio.0c00184

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OCA

[1] 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

[2] 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:https://dx.doi.org/10.1021/acschembio.0c00184

[1]

[2]

@@ Line 3: / Line 3: @@
 <StructureSection load='6vv3' size='340' side='right'caption='[[6vv3]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6vv3]] 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=6VV3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VV3 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6vv3]] 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=6VV3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VV3 FirstGlance]. <br>
-</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=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=RM7:2-[(4-amino-6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-2-yl)sulfanyl]-N-[2-(piperidin-1-yl)ethyl]acetamide'>RM7</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.4&#8491;</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='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=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=RM7:2-[(4-amino-6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-2-yl)sulfanyl]-N-[2-(piperidin-1-yl)ethyl]acetamide'>RM7</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=6vv3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vv3 OCA], [https://pdbe.org/6vv3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vv3 RCSB], [https://www.ebi.ac.uk/pdbsum/6vv3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vv3 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>
+[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 ==
@@ Line 24: / Line 24: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Myctu]]
+[[Category: Mycobacterium tuberculosis H37Rv]]
-[[Category: Garneau-Tsodikova, S]]
+[[Category: Garneau-Tsodikova S]]
-[[Category: Hou, C]]
+[[Category: Hou C]]
-[[Category: Ngo, H X]]
+[[Category: Ngo HX]]
-[[Category: Punetha, A]]
+[[Category: Punetha A]]
-[[Category: Tsodikov, O V]]
+[[Category: Tsodikov OV]]
-[[Category: Acetyltransferase]]
-[[Category: Aminoglycoside]]
-[[Category: Competitive]]
-[[Category: Resistance]]
-[[Category: Transferase]]
-[[Category: Transferase-transferase inhibitor complex]]

6vv3: Difference between revisions

Latest revision as of 08:20, 11 October 2023

Crystal structure of Eis from Mycobacterium tuberculosis in complex with inhibitor SGT1358

Structural highlights

Function

Publication Abstract from PubMed

References

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