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

  1. Lira-Navarrete, E. 1
  2. Iglesias-Fernández, J. 3
  3. Zandberg, W.F. 5
  4. Compañón, I. 4
  5. Kong, Y. 2
  6. Corzana, F. 4
  7. Pinto, B.M. 5
  8. Clausen, H. 2
  9. Peregrina, J.M. 4
  10. Vocadlo, D.J. 5
  11. Rovira, C. 36
  12. Hurtado-Guerrero, R. 1
  1. 1 Universidad de Zaragoza
    info

    Universidad de Zaragoza

    Zaragoza, España

    ROR https://ror.org/012a91z28

  2. 2 University of Copenhagen
    info

    University of Copenhagen

    Copenhague, Dinamarca

    ROR https://ror.org/035b05819

  3. 3 Universitat de Barcelona
    info

    Universitat de Barcelona

    Barcelona, España

    ROR https://ror.org/021018s57

  4. 4 Universidad de La Rioja
    info

    Universidad de La Rioja

    Logroño, España

    ROR https://ror.org/0553yr311

  5. 5 Simon Fraser University
    info

    Simon Fraser University

    Burnaby, Canadá

    ROR https://ror.org/0213rcc28

  6. 6 Institució Catalana de Recerca i Estudis Avançats
    info

    Institució Catalana de Recerca i Estudis Avançats

    Barcelona, España

    ROR https://ror.org/0371hy230

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Revista:
Angewandte Chemie International

ISSN: 1433-7851

Año de publicación: 2014

Volumen: 53

Número: 31

Páginas: 8206-8210

Tipo: Artículo

DOI: 10.1002/ANIE.201402781 SCOPUS: 2-s2.0-84905366680 WoS: WOS:000340520700042 GOOGLE SCHOLAR lock_openAcceso abierto editor

Otras publicaciones en: Angewandte Chemie International

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2013/00007/001

Resumen

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 SNi-type reaction in which the substrate N-acetyl sugar substituent coordinates efficient glycosyl transfer. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.