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6rkq
From Proteopedia
(Difference between revisions)
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| - | ==Crystal Structure of TGT in complex with | + | ==Crystal Structure of TGT in complex with N2-methyl-8-(prop-1-yn-1-yl)-3H,7H,8H-imidazo[4,5-g]quinazoline-2,6-diamine== |
| - | <StructureSection load='6rkq' size='340' side='right'caption='[[6rkq]]' scene=''> | + | <StructureSection load='6rkq' size='340' side='right'caption='[[6rkq]], [[Resolution|resolution]] 1.67Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RKQ OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6RKQ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6rkq]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Zymmo Zymmo]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RKQ OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6RKQ FirstGlance]. <br> |
| - | </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=6rkq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rkq OCA], [http://pdbe.org/6rkq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6rkq RCSB], [http://www.ebi.ac.uk/pdbsum/6rkq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6rkq ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K75:(8~{R})-~{N}2-methyl-8-prop-1-ynyl-7,8-dihydro-3~{H}-imidazo[4,5-g]quinazoline-2,6-diamine'>K75</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">tgt, ZMO0363 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=264203 ZYMMO])</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(34)_transglycosylase tRNA-guanine(34) transglycosylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.29 2.4.2.29] </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=6rkq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rkq OCA], [http://pdbe.org/6rkq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6rkq RCSB], [http://www.ebi.ac.uk/pdbsum/6rkq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6rkq ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/TGT_ZYMMO TGT_ZYMMO]] Exchanges the guanine residue with 7-aminomethyl-7-deazaguanine in tRNAs with GU(N) anticodons (tRNA-Asp, -Asn, -His and -Tyr). After this exchange, a cyclopentendiol moiety is attached to the 7-aminomethyl group of 7-deazaguanine, resulting in the hypermodified nucleoside queuosine (Q) (7-(((4,5-cis-dihydroxy-2-cyclopenten-1-yl)amino)methyl)-7-deazaguanosine).[HAMAP-Rule:MF_00168] | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Fragment-based lead discovery was applied to tRNA-guanine transglycosylase, an enzyme modifying post-transcriptionally tRNAs in Shigella, the causative agent of shigellosis. TGT inhibition prevents translation of Shigella's virulence factor VirF, hence reducing pathogenicity. One discovered fragment opens a transient subpocket in the preQ1-recognition site by pushing back an aspartate residue. This step is associated with reorganization of further amino acids structurally transforming a loop adjacent to the recognition site by duplicating the volume of the preQ1-recognition pocket. We synthesized 6-carboxamido-, 6-hydrazido-, and 4-guanidino-benzimidazoles to target the opened pocket, including a dihydro-imidazoquinazoline with a propyn-1-yl exit vector pointing into the transient pocket and displacing a conserved water network. MD simulations and hydration-site analysis suggest water displacement to contribute favorably to ligand binding. A cysteine residue, exclusively present in bacterial TGTs, serves as gatekeeper of the transient subpocket. It becomes accessible upon pocket opening for selective covalent attachment of electrophilic ligands in eubacterial TGTs. | ||
| + | |||
| + | Fragment Screening Hit Draws Attention to a Novel Transient Pocket Adjacent to the Recognition Site of the tRNA-Modifying Enzyme TGT.,Hassaan E, Hohn C, Ehrmann FR, Goetzke FW, Movsisyan L, Hufner-Wulsdorf T, Sebastiani M, Hartsch A, Reuter K, Diederich F, Klebe G J Med Chem. 2020 Jul 9;63(13):6802-6820. doi: 10.1021/acs.jmedchem.0c00115. Epub , 2020 Jun 25. PMID:32515955<ref>PMID:32515955</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6rkq" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Hassaan, E | + | [[Category: Zymmo]] |
| + | [[Category: Hassaan, E]] | ||
| + | [[Category: Heine, A]] | ||
| + | [[Category: Klebe, G]] | ||
| + | [[Category: Guanine exchange enzyme]] | ||
| + | [[Category: Protein interface]] | ||
| + | [[Category: Tgt]] | ||
| + | [[Category: Transferase]] | ||
| + | [[Category: Transglycosylase]] | ||
| + | [[Category: Trna]] | ||
Revision as of 12:44, 16 December 2020
Crystal Structure of TGT in complex with N2-methyl-8-(prop-1-yn-1-yl)-3H,7H,8H-imidazo[4,5-g]quinazoline-2,6-diamine
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