Document Detail


Flexible adaptations in the structure of the tRNA-modifying enzyme tRNA-guanine transglycosylase and their implications for substrate selectivity, reaction mechanism and structure-based drug design.
MedLine Citation:
PMID:  14523925     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The enzyme tRNA-guanine transglycosylase (TGT, EC 2.4.2.29) catalyses a base-exchange reaction that leads to anticodon modifications of certain tRNAs. The TGT enzymes of the eubacteria Zymomonas mobilis (Z. mobilis TGT) and Escherichia coli (E. coli TGT) show a different behaviour in the presence of competitive inhibitors. The active sites of both enzymes are identical apart from a single conservative amino acid exchange, namely Tyr106 of Z. mobilis TGT is replaced by a Phe in E. coli TGT. Although Tyr106 is, in contrast to Phe106, hydrogen bonded in the ligand-free structure, we can show by a mutational study of TGT(Y106F) that this is not the reason for the different responses upon competition. The TGT enzymes of various species differ in their substrate selectivity. Depending on the applied pH conditions and/or induced by ligand binding, a peptide-bond flip modulates the recognition properties of the substrate binding site, which changes between donor and acceptor functionality. Furthermore interstitial water molecules play an important role in these adaptations of the pocket. The flip of the peptide bond is further stabilised by a glutamate residue that operates as general acid/base. An active-site aspartate residue, presumed to operate as a nucleophile through covalent bonding during the base-exchange reaction, shows different conformations depending on the nature of the bound ligand. The induced-fit adaptations observed in the various TGT complex structures by multiple crystal-structure analyses are in agreement with the functional properties of the enzyme. In consequence, full understanding of this plasticity can be exploited for drug design.
Authors:
Ruth Brenk; Milton T Stubbs; Andreas Heine; Klaus Reuter; Gerhard Klebe
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Chembiochem : a European journal of chemical biology     Volume:  4     ISSN:  1439-4227     ISO Abbreviation:  Chembiochem     Publication Date:  2003 Oct 
Date Detail:
Created Date:  2003-10-02     Completed Date:  2004-11-04     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  100937360     Medline TA:  Chembiochem     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  1066-77     Citation Subset:  IM    
Affiliation:
Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, 35032 Marburg, Germany.
Data Bank Information
Bank Name/Acc. No.:
PDB/1OZM;  1OZQ;  1P0B;  1P0D;  1P0E
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MeSH Terms
Descriptor/Qualifier:
Aspartic Acid / chemistry
Base Sequence
Binding Sites
Crystallography, X-Ray
Drug Design
Escherichia coli
Glutamic Acid / chemistry
Models, Molecular
Molecular Sequence Data
Pentosyltransferases / antagonists & inhibitors,  chemistry*,  metabolism
Peptides / chemistry,  metabolism
Protein Folding
RNA, Transfer / chemistry*,  metabolism
Substrate Specificity
Zymomonas
Chemical
Reg. No./Substance:
0/Peptides; 56-84-8/Aspartic Acid; 56-86-0/Glutamic Acid; 9014-25-9/RNA, Transfer; EC 2.4.2.-/Pentosyltransferases; EC 2.4.2.29/queuine tRNA-ribosyltransferase

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


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