6rkq

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

spinqualitylabelsall models 6rkq, resolution 1.67Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6rkq is a 1 chain structure with sequence from Zymomonas mobilis subsp. mobilis ZM4 = ATCC 31821. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.665Å Ligands: DMS, GOL, K75, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also TRNA-guanine transglycosylase 3D structures

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