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==Crystal structure of TrmD from Pseudomonas aeruginosa in complex with active-site inhibitor== | ==Crystal structure of TrmD from Pseudomonas aeruginosa in complex with active-site inhibitor== | ||
<StructureSection load='5zhm' size='340' side='right' | <StructureSection load='5zhm' size='340' side='right'caption='[[5zhm]], [[Resolution|resolution]] 2.76Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5zhm]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ZHM OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[5zhm]] 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=5ZHM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ZHM FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9D3:N-({4-[(diethylamino)methyl]phenyl}methyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-5-carboxamide'>9D3</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.76Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9D3:N-({4-[(diethylamino)methyl]phenyl}methyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-5-carboxamide'>9D3</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'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5zhm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zhm OCA], [https://pdbe.org/5zhm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5zhm RCSB], [https://www.ebi.ac.uk/pdbsum/5zhm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5zhm ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == 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 == | |||
Among the >120 modified ribonucleosides in the prokaryotic epitranscriptome, many tRNA modifications are critical to bacterial survival, which makes their synthetic enzymes ideal targets for antibiotic development. Here we performed a structure-based design of inhibitors of tRNA-(N(1)G37) methyltransferase, TrmD, which is an essential enzyme in many bacterial pathogens. On the basis of crystal structures of TrmDs from Pseudomonas aeruginosa and Mycobacterium tuberculosis, we synthesized a series of thienopyrimidinone derivatives with nanomolar potency against TrmD in vitro and discovered a novel active site conformational change triggered by inhibitor binding. This tyrosine-flipping mechanism is uniquely found in P. aeruginosa TrmD and renders the enzyme inaccessible to the cofactor S-adenosyl-l-methionine (SAM) and probably to the substrate tRNA. Biophysical and biochemical structure-activity relationship studies provided insights into the mechanisms underlying the potency of thienopyrimidinones as TrmD inhibitors, with several derivatives found to be active against Gram-positive and mycobacterial pathogens. These results lay a foundation for further development of TrmD inhibitors as antimicrobial agents. | |||
Thienopyrimidinone Derivatives That Inhibit Bacterial tRNA (Guanine37-N(1))-Methyltransferase (TrmD) by Restructuring the Active Site with a Tyrosine-Flipping Mechanism.,Zhong W, Pasunooti KK, Balamkundu S, Wong YH, Nah Q, Gadi V, Gnanakalai S, Chionh YH, McBee ME, Gopal P, Lim SH, Olivier N, Buurman ET, Dick T, Liu CF, Lescar J, Dedon PC J Med Chem. 2019 Sep 12;62(17):7788-7805. doi: 10.1021/acs.jmedchem.9b00582. Epub , 2019 Aug 29. PMID:31442049<ref>PMID:31442049</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5zhm" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[TRNA methyltransferase 3D structures|TRNA methyltransferase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Pseudomonas aeruginosa UCBPP-PA14]] | ||
[[Category: | [[Category: Balamkundu S]] | ||
[[Category: | [[Category: Dedon PC]] | ||
[[Category: | [[Category: Lescar J]] | ||
[[Category: | [[Category: Liu CF]] | ||
[[Category: | [[Category: Nah Q]] | ||
[[Category: | [[Category: Pasunooti KK]] | ||
[[Category: | [[Category: Wong YW]] | ||
[[Category: | [[Category: Zhong W]] | ||
Latest revision as of 11:55, 22 November 2023
Crystal structure of TrmD from Pseudomonas aeruginosa in complex with active-site inhibitorCrystal structure of TrmD from Pseudomonas aeruginosa in complex with active-site inhibitor
Structural highlights
FunctionTRMD_PSEAB Specifically methylates guanosine-37 in various tRNAs. Publication Abstract from PubMedAmong the >120 modified ribonucleosides in the prokaryotic epitranscriptome, many tRNA modifications are critical to bacterial survival, which makes their synthetic enzymes ideal targets for antibiotic development. Here we performed a structure-based design of inhibitors of tRNA-(N(1)G37) methyltransferase, TrmD, which is an essential enzyme in many bacterial pathogens. On the basis of crystal structures of TrmDs from Pseudomonas aeruginosa and Mycobacterium tuberculosis, we synthesized a series of thienopyrimidinone derivatives with nanomolar potency against TrmD in vitro and discovered a novel active site conformational change triggered by inhibitor binding. This tyrosine-flipping mechanism is uniquely found in P. aeruginosa TrmD and renders the enzyme inaccessible to the cofactor S-adenosyl-l-methionine (SAM) and probably to the substrate tRNA. Biophysical and biochemical structure-activity relationship studies provided insights into the mechanisms underlying the potency of thienopyrimidinones as TrmD inhibitors, with several derivatives found to be active against Gram-positive and mycobacterial pathogens. These results lay a foundation for further development of TrmD inhibitors as antimicrobial agents. Thienopyrimidinone Derivatives That Inhibit Bacterial tRNA (Guanine37-N(1))-Methyltransferase (TrmD) by Restructuring the Active Site with a Tyrosine-Flipping Mechanism.,Zhong W, Pasunooti KK, Balamkundu S, Wong YH, Nah Q, Gadi V, Gnanakalai S, Chionh YH, McBee ME, Gopal P, Lim SH, Olivier N, Buurman ET, Dick T, Liu CF, Lescar J, Dedon PC J Med Chem. 2019 Sep 12;62(17):7788-7805. doi: 10.1021/acs.jmedchem.9b00582. Epub , 2019 Aug 29. PMID:31442049[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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