6rkt: Difference between revisions
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==Crystal Structure of TGT in complex with | ==Crystal Structure of TGT in complex with N2-methyl-1H,7H,8H-imidazo[4,5-g]quinazoline-2,6-diamine== | ||
<StructureSection load='6rkt' size='340' side='right'caption='[[6rkt]]' scene=''> | <StructureSection load='6rkt' size='340' side='right'caption='[[6rkt]], [[Resolution|resolution]] 1.75Å' 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=6RKT OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6RKT FirstGlance]. <br> | <table><tr><td colspan='2'>[[6rkt]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"achromobacter_anaerobium"_(sic)_shimwell_1937 "achromobacter anaerobium" (sic) shimwell 1937]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RKT OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6RKT 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=6rkt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rkt OCA], [http://pdbe.org/6rkt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6rkt RCSB], [http://www.ebi.ac.uk/pdbsum/6rkt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6rkt 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=K7H:~{N}2-methyl-7,8-dihydro-3~{H}-imidazo[4,5-g]quinazoline-2,6-diamine'>K7H</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=542 "Achromobacter anaerobium" (sic) Shimwell 1937])</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=6rkt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rkt OCA], [http://pdbe.org/6rkt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6rkt RCSB], [http://www.ebi.ac.uk/pdbsum/6rkt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6rkt 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 6rkt" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Hassaan, E | [[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 15:44, 16 December 2020
Crystal Structure of TGT in complex with N2-methyl-1H,7H,8H-imidazo[4,5-g]quinazoline-2,6-diamineCrystal Structure of TGT in complex with N2-methyl-1H,7H,8H-imidazo[4,5-g]quinazoline-2,6-diamine
Structural highlights
Function[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] Publication Abstract from PubMedFragment-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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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