7bgg
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of the heterocyclic toxin methyltransferase from Mycobacterium tuberculosis== | |
| + | <StructureSection load='7bgg' size='340' side='right'caption='[[7bgg]], [[Resolution|resolution]] 1.04Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[7bgg]] 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=7BGG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7BGG 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]] 1.04Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</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=7bgg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7bgg OCA], [https://pdbe.org/7bgg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7bgg RCSB], [https://www.ebi.ac.uk/pdbsum/7bgg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7bgg ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/HTM_MYCTU HTM_MYCTU] Involved in cellular response to chemical stress and may contribute to resistance toward antimicrobial natural compounds as well as drugs (Probable). Catalyzes the methylation and detoxification of the P.aeruginosa toxin 2-heptyl-1-hydroxy-4(1H)-quinolinone (HQNO) to 2-heptyl-1-methoxy-4(1H)-quinolinone (HMOQ) (PubMed:33064871). Can also methylate 3-bromo-2-heptyl-1-hydroxy-4(1H)-quinolinone, and shows much lower activity with 1-hydroxyquinolin-4(1H)-one, quercetin, 4-hydroxyquinolin-2(1H)-one (DHQ) and 4-hydroxyisoquinolin-1(2H)-one (PubMed:33064871). In addition, N-methylates and abolishes the mycobactericidal activity of 3-methyl-1-oxo-2-[3-oxo-3-(pyrrolidin-1-yl)propyl]-1,5-dihydrobenzo[4,5]imidazo[1,2-a]pyridine-4-carbonitrile (compound 14), an inhibitor of DprE1 (PubMed:27432954). Also methylates and reduces the inhibitory effect of TPSA (2-[5-(2-{[4-(2-thienyl)-2-pyrimidinyl]sulfanyl}acetyl)-2-thienyl]acetic acid), an inhibitor of GlmU acetyltransferase (PubMed:31380295).<ref>PMID:27432954</ref> <ref>PMID:31380295</ref> <ref>PMID:33064871</ref> <ref>PMID:33064871</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The S-adenosyl-L-methionine-dependent methyltransferase Rv0560c of Mycobacterium tuberculosis belongs to an orthologous group of heterocyclic toxin methyltransferases (Htm) which likely contribute to resistance of mycobacteria towards antimicrobial natural compounds as well as drugs. HtmM.t. catalyzes the methylation of the Pseudomonas aeruginosa toxin 2-heptyl-1-hydroxyquinolin-4(1H)-one (also known as 2-heptyl-4-hydroxyquinoline N-oxide), a potent inhibitor of respiratory electron transfer, its 1-hydroxyquinolin-4(1H)-one core (QNO), structurally related (iso)quinolones, and some mycobactericidal compounds. In this study, crystal structures of HtmM.t. in complex with S-adenosyl-L-homocysteine (SAH) and the methyl-accepting substrates QNO or 4-hydroxyisoquinoline-1(2H)-one, or the methylated product 1-methoxyquinolin-4(1H)-one, were determined at < 1.9 A resolution. The monomeric protein exhibits the typical Rossmann fold topology and conserved residues of class I methyltransferases. Its SAH binding pocket is connected via a short tunnel to a large solvent-accessible cavity, which accommodates the methyl-accepting substrate. Residues W44, F168, and F208 in connection with F212 form a hydrophobic clamp around the heteroaromatic ring of the methyl-accepting substrate and likely play a major role in substrate positioning. Structural and biochemical data suggest that H139 and T136 are key active site residues, with H139 acting as general base that activates the methyl-accepting hydroxy group. Our structural data may contribute to the design of Htm inhibitors or of antimycobacterial drugs unamenable for methylation. | ||
| - | + | Structural basis of O-methylation of (2-heptyl-)1-hydroxyquinolin-4(1H)-one and related compounds by the heterocyclic toxin methyltransferase Rv0560c of Mycobacterium tuberculosis.,Sartor P, Denkhaus L, Gerhardt S, Einsle O, Fetzner S J Struct Biol. 2021 Sep 20;213(4):107794. doi: 10.1016/j.jsb.2021.107794. PMID:34506908<ref>PMID:34506908</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 7bgg" style="background-color:#fffaf0;"></div> |
| - | [[Category: Denkhaus | + | == References == |
| - | [[Category: Fetzner | + | <references/> |
| - | [[Category: | + | __TOC__ |
| - | [[Category: Sartor | + | </StructureSection> |
| + | [[Category: Large Structures]] | ||
| + | [[Category: Mycobacterium tuberculosis H37Rv]] | ||
| + | [[Category: Denkhaus L]] | ||
| + | [[Category: Einsle O]] | ||
| + | [[Category: Fetzner S]] | ||
| + | [[Category: Gerhardt S]] | ||
| + | [[Category: Sartor P]] | ||
Current revision
Crystal structure of the heterocyclic toxin methyltransferase from Mycobacterium tuberculosis
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