4leq

From Proteopedia

tRNA guanine transglycosylase (TGT) in complex with Furanoside-Based lin-Benzoguanine 1

PDB ID 4leq

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Structural highlights

4leq 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 1.405Å
Ligands:	, , ,
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

The enzyme tRNA-guanine transglycosylase has been identified as a drug target for the foodborne illness shigellosis. A key challenge in structure-based design for this enzyme is the filling of the polar ribose-34 pocket. Herein, we describe a novel series of ligands consisting of furanoside-appended lin-benzoguanines. They were designed to replace a conserved water cluster and differ by the functional groups at C(2) and C(3) of the furanosyl moiety being either OH or OMe. The unfavorable desolvation of Asp102 and Asp280, which are located close to the ribose-34 pocket, had a significant impact on binding affinity. While the enzyme has tRNA as its natural substrate, X-ray co-crystal structures revealed that the furanosyl moieties of the ligands are not accommodated in the tRNA ribose-34 site, but at the location of the adjacent phosphate group. A remarkable similarity of the position of the oxygen atoms in these two structures suggests furanosides as a potential phosphate isoster.

Replacement of Water Molecules in a Phosphate Binding Site by Furanoside-Appended lin-Benzoguanine Ligands of tRNA-Guanine Transglycosylase (TGT).,Barandun LJ, Ehrmann FR, Zimmerli D, Immekus F, Giroud M, Grunenfelder C, Schweizer WB, Bernet B, Betz M, Heine A, Klebe G, Diederich F Chemistry. 2015 Jan 2;21(1):126-35. doi: 10.1002/chem.201405764. Epub 2014 Dec 5. PMID:25483606^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Barandun LJ, Ehrmann FR, Zimmerli D, Immekus F, Giroud M, Grunenfelder C, Schweizer WB, Bernet B, Betz M, Heine A, Klebe G, Diederich F. Replacement of Water Molecules in a Phosphate Binding Site by Furanoside-Appended lin-Benzoguanine Ligands of tRNA-Guanine Transglycosylase (TGT). Chemistry. 2015 Jan 2;21(1):126-35. doi: 10.1002/chem.201405764. Epub 2014 Dec 5. PMID:25483606 doi:http://dx.doi.org/10.1002/chem.201405764