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==Crystal structure of TrmD, a tRNA-(N1G37) methyltransferase, from Mycobacterium abscessus in complex with Fragment 19 (5-fluoroquinazolin-4-ol)== | |||
<StructureSection load='6qop' size='340' side='right'caption='[[6qop]], [[Resolution|resolution]] 1.91Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6qop]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/"mycobacterium_abcessus"_moore_and_frerichs_1953 "mycobacterium abcessus" moore and frerichs 1953]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6QOP OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6QOP FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=JBQ:5-fluoranyl-3,4-dihydroquinazolin-4-ol'>JBQ</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6nvr|6nvr]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">trmD, MAB_3226c ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=36809 "Mycobacterium abcessus" Moore and Frerichs 1953])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/tRNA_(guanine(37)-N(1))-methyltransferase tRNA (guanine(37)-N(1))-methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.228 2.1.1.228] </span></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=6qop FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qop OCA], [http://pdbe.org/6qop PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6qop RCSB], [http://www.ebi.ac.uk/pdbsum/6qop PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6qop ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/B1MDI3_MYCA9 B1MDI3_MYCA9]] Specifically methylates guanosine-37 in various tRNAs.[HAMAP-Rule:MF_00605][RuleBase:RU003464][SAAS:SAAS00040552] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Translational frameshift errors are often deleterious to the synthesis of functional proteins and could therefore be promoted therapeutically to kill bacteria. TrmD (tRNA-(N(1)G37) methyltransferase) is an essential tRNA modification enzyme in bacteria that prevents +1 errors in the reading frame during protein translation and represents an attractive potential target for the development of new antibiotics. Here, we describe the application of a structure-guided fragment-based drug discovery approach to the design of a new class of inhibitors against TrmD in Mycobacterium abscessus. Fragment library screening, followed by structure-guided chemical elaboration of hits, led to the rapid development of drug-like molecules with potent in vitro TrmD inhibitory activity. Several of these compounds exhibit activity against planktonic M. abscessus and M. tuberculosis as well as against intracellular M. abscessus and M. leprae, indicating their potential as the basis for a novel class of broad-spectrum mycobacterial drugs. | |||
Fragment-based discovery of a new class of inhibitors targeting mycobacterial tRNA modification.,Thomas SE, Whitehouse AJ, Brown K, Burbaud S, Belardinelli JM, Sangen J, Lahiri R, Libardo MDJ, Gupta P, Malhotra S, Boshoff HIM, Jackson M, Abell C, Coyne AG, Blundell TL, Floto RA, Mendes V Nucleic Acids Res. 2020 Jun 30. pii: 5865065. doi: 10.1093/nar/gkaa539. PMID:32602532<ref>PMID:32602532</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Blundell, T | <div class="pdbe-citations 6qop" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[TRNA methyltransferase 3D structures|TRNA methyltransferase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Mycobacterium abcessus moore and frerichs 1953]] | |||
[[Category: Large Structures]] | |||
[[Category: Abell, C]] | |||
[[Category: Blundell, T L]] | |||
[[Category: Coyne, A G]] | |||
[[Category: Mendes, V]] | [[Category: Mendes, V]] | ||
[[Category: Thomas, S | [[Category: Thomas, S E]] | ||
[[Category: | [[Category: Whitehouse, A J]] | ||
[[Category: | [[Category: Spout methyltransferase]] | ||
[[Category: | [[Category: Transferase]] | ||
[[Category: Trmd]] | |||
[[Category: Trna methyltransferase]] | |||
Latest revision as of 08:49, 5 August 2020
Crystal structure of TrmD, a tRNA-(N1G37) methyltransferase, from Mycobacterium abscessus in complex with Fragment 19 (5-fluoroquinazolin-4-ol)Crystal structure of TrmD, a tRNA-(N1G37) methyltransferase, from Mycobacterium abscessus in complex with Fragment 19 (5-fluoroquinazolin-4-ol)
Structural highlights
Function[B1MDI3_MYCA9] Specifically methylates guanosine-37 in various tRNAs.[HAMAP-Rule:MF_00605][RuleBase:RU003464][SAAS:SAAS00040552] Publication Abstract from PubMedTranslational frameshift errors are often deleterious to the synthesis of functional proteins and could therefore be promoted therapeutically to kill bacteria. TrmD (tRNA-(N(1)G37) methyltransferase) is an essential tRNA modification enzyme in bacteria that prevents +1 errors in the reading frame during protein translation and represents an attractive potential target for the development of new antibiotics. Here, we describe the application of a structure-guided fragment-based drug discovery approach to the design of a new class of inhibitors against TrmD in Mycobacterium abscessus. Fragment library screening, followed by structure-guided chemical elaboration of hits, led to the rapid development of drug-like molecules with potent in vitro TrmD inhibitory activity. Several of these compounds exhibit activity against planktonic M. abscessus and M. tuberculosis as well as against intracellular M. abscessus and M. leprae, indicating their potential as the basis for a novel class of broad-spectrum mycobacterial drugs. Fragment-based discovery of a new class of inhibitors targeting mycobacterial tRNA modification.,Thomas SE, Whitehouse AJ, Brown K, Burbaud S, Belardinelli JM, Sangen J, Lahiri R, Libardo MDJ, Gupta P, Malhotra S, Boshoff HIM, Jackson M, Abell C, Coyne AG, Blundell TL, Floto RA, Mendes V Nucleic Acids Res. 2020 Jun 30. pii: 5865065. doi: 10.1093/nar/gkaa539. PMID:32602532[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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