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Substrate-guided front-face reaction revealed by combined structural snapshots and metadynamics for the polypeptide N-acetylgalactosaminyltransferase 2.

Authors
  • Lira-Navarrete, Erandi
  • Iglesias-Fernández, Javier
  • Zandberg, Wesley F
  • Compañón, Ismael
  • Kong, Yun
  • Corzana, Francisco
  • Pinto, B Mario
  • Clausen, Henrik
  • Peregrina, Jesús M
  • Vocadlo, David J
  • Rovira, Carme
  • Hurtado-Guerrero, Ramon
Type
Published Article
Journal
Angewandte Chemie International Edition in English
Publisher
Wiley (John Wiley & Sons)
Publication Date
Jul 28, 2014
Volume
53
Issue
31
Pages
8206–8210
Identifiers
DOI: 10.1002/anie.201402781
PMID: 24954443
Source
Medline
Keywords
License
Unknown

Abstract

The retaining glycosyltransferase GalNAc-T2 is a member of a large family of human polypeptide GalNAc-transferases that is responsible for the post-translational modification of many cell-surface proteins. By the use of combined structural and computational approaches, we provide the first set of structural snapshots of the enzyme during the catalytic cycle and combine these with quantum-mechanics/molecular-mechanics (QM/MM) metadynamics to unravel the catalytic mechanism of this retaining enzyme at the atomic-electronic level of detail. Our study provides a detailed structural rationale for an ordered bi-bi kinetic mechanism and reveals critical aspects of substrate recognition, which dictate the specificity for acceptor Thr versus Ser residues and enforce a front-face SN i-type reaction in which the substrate N-acetyl sugar substituent coordinates efficient glycosyl transfer.

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