View source for 5zhl


==Crystal structure of TrmD from Mycobacterium tuberculosis in complex with active-site inhibitor==
<StructureSection load='5zhl' size='340' side='right'caption='[[5zhl]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5zhl]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_CDC1551 Mycobacterium tuberculosis CDC1551]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ZHL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ZHL 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]] 2.25&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9D0:N-({4-[(octylamino)methyl]phenyl}methyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-5-carboxamide'>9D0</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=5zhl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zhl OCA], [https://pdbe.org/5zhl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5zhl RCSB], [https://www.ebi.ac.uk/pdbsum/5zhl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5zhl ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/TRMD_MYCTU TRMD_MYCTU] Specifically methylates guanosine-37 in various tRNAs.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Among the &gt;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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5zhl" style="background-color:#fffaf0;"></div>

==See Also==
*[[TRNA methyltransferase 3D structures|TRNA methyltransferase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Mycobacterium tuberculosis CDC1551]]
[[Category: Balamkundu S]]
[[Category: Dedon PC]]
[[Category: Lescar J]]
[[Category: Liu CF]]
[[Category: Nah Q]]
[[Category: Pasunooti KK]]
[[Category: Wong YW]]
[[Category: Zhong W]]