6afk: Difference between revisions

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-'''Unreleased structure'''
-The entry 6afk is ON HOLD
+==Crystal structure of TrmD from Pseudomonas aeruginosa in complex with active-site inhibitor==
+<StructureSection load='6afk' size='340' side='right'caption='[[6afk]], [[Resolution|resolution]] 2.75&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6afk]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa_UCBPP-PA14 Pseudomonas aeruginosa UCBPP-PA14]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6AFK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6AFK 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]] 2.75&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9WO:N-{(3S)-1-[3-(pyridin-4-yl)-1H-pyrazol-5-yl]piperidin-3-yl}-1H-indole-2-carboxamide'>9WO</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</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=6afk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6afk OCA], [https://pdbe.org/6afk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6afk RCSB], [https://www.ebi.ac.uk/pdbsum/6afk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6afk ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/TRMD_PSEAB TRMD_PSEAB] Specifically methylates guanosine-37 in various tRNAs.
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Bacterial tRNA modification synthesis pathways are critical to cell survival under stress and thus represent ideal mechanism-based targets for antibiotic development. One such target is the tRNA-(N(1)G37) methyltransferase (TrmD), which is conserved and essential in many bacterial pathogens. Here we developed and applied a widely applicable, radioactivity-free, bioluminescence-based high-throughput screen (HTS) against 116350 compounds from structurally diverse small-molecule libraries to identify inhibitors of Pseudomonas aeruginosa TrmD ( PaTrmD). Of 285 compounds passing primary and secondary screens, a total of 61 TrmD inhibitors comprised of more than 12 different chemical scaffolds were identified, all showing submicromolar to low micromolar enzyme inhibitor constants, with binding affinity confirmed by thermal stability and surface plasmon resonance. S-Adenosyl-l-methionine (SAM) competition assays suggested that compounds in the pyridine-pyrazole-piperidine scaffold were substrate SAM-competitive inhibitors. This was confirmed in structural studies, with nuclear magnetic resonance analysis and crystal structures of PaTrmD showing pyridine-pyrazole-piperidine compounds bound in the SAM-binding pocket. Five hits showed cellular activities against Gram-positive bacteria, including mycobacteria, while one compound, a SAM-noncompetitive inhibitor, exhibited broad-spectrum antibacterial activity. The results of this HTS expand the repertoire of TrmD-inhibiting molecular scaffolds that show promise for antibiotic development.
-Authors: Zhong, W., Koay, A., Wong, Y.W., Sahili, A.E., Nah, Q., Kang, C., Poulsen, A., Chionh, Y.K., McBee, M., Matter, A., Hill, J., Lescar, J., Dedon, P.C.
+Targeting the Bacterial Epitranscriptome for Antibiotic Development: Discovery of Novel tRNA-(N(1)G37) Methyltransferase (TrmD) Inhibitors.,Zhong W, Koay A, Ngo A, Li Y, Nah Q, Wong YH, Chionh YH, Ng HQ, Koh-Stenta X, Poulsen A, Foo K, McBee M, Choong ML, El Sahili A, Kang C, Matter A, Lescar J, Hill J, Dedon P ACS Infect Dis. 2019 Mar 8;5(3):326-335. doi: 10.1021/acsinfecdis.8b00275. Epub, 2019 Feb 4. PMID:30682246<ref>PMID:30682246</ref>
-Description: Crystal structure of TrmD from Pseudomonas aeruginosa in complex with active-site inhibitor
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Hill, J]]
+<div class="pdbe-citations 6afk" style="background-color:#fffaf0;"></div>
-[[Category: Lescar, J]]
-[[Category: Matter, A]]
+==See Also==
-[[Category: Poulsen, A]]
+*[[TRNA methyltransferase 3D structures|TRNA methyltransferase 3D structures]]
-[[Category: Mcbee, M]]
+== References ==
-[[Category: Wong, Y.W]]
+<references/>
-[[Category: Koay, A]]
+__TOC__
-[[Category: Kang, C]]
+</StructureSection>
-[[Category: Nah, Q]]
+[[Category: Large Structures]]
-[[Category: Sahili, A.E]]
+[[Category: Pseudomonas aeruginosa UCBPP-PA14]]
-[[Category: Dedon, P.C]]
+[[Category: Chionh YK]]
-[[Category: Zhong, W]]
+[[Category: Dedon PC]]
-[[Category: Chionh, Y.K]]
+[[Category: Hill J]]
+[[Category: Kang C]]
+[[Category: Koay A]]
+[[Category: Lescar J]]
+[[Category: Matter A]]
+[[Category: McBee M]]
+[[Category: Nah Q]]
+[[Category: Poulsen A]]
+[[Category: Sahili AE]]
+[[Category: Wong YW]]
+[[Category: Zhong W]]