Substrate-Guided Front-Face Reaction Revealed by Combined Structural Snapshots and Metadynamics for the Polypeptide N-Acetylgalactosaminyltransferase 2

Erandi Lira-Navarrete; Javier Iglesias-Fernández; Wesley F Zandberg; Ismael Compañón; Yun Kong; Francisco Corzana; B Mario Pinto; Henrik Clausen; Jesús M Peregrina; David J Vocadlo; Carme Rovira; Ramon Hurtado-Guerrero

doi:10.1002/anie.201402781

Substrate-Guided Front-Face Reaction Revealed by Combined Structural Snapshots and Metadynamics for the Polypeptide N-Acetylgalactosaminyltransferase 2

Erandi Lira-Navarrete, Javier Iglesias-Fernández, Wesley F Zandberg, Ismael Compañón, Yun Kong, Francisco Corzana, B Mario Pinto, Henrik Clausen, Jesús M Peregrina, David J Vocadlo, Carme Rovira, Ramon Hurtado-Guerrero

Glycomics Program

57 Citations (Scopus)

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.

Original language	English
Journal	Angewandte Chemie (International ed. in English)
Volume	53
Issue number	31
Pages (from-to)	8206-8210
Number of pages	5
ISSN	1433-7851
DOIs	https://doi.org/10.1002/anie.201402781
Publication status	Published - 28 Jul 2014

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Lira-Navarrete, E., Iglesias-Fernández, J., Zandberg, W. F., Compañón, I., Kong, Y., Corzana, F., Pinto, B. M., Clausen, H., Peregrina, J. M., Vocadlo, D. J., Rovira, C., & Hurtado-Guerrero, R. (2014). Substrate-Guided Front-Face Reaction Revealed by Combined Structural Snapshots and Metadynamics for the Polypeptide N-Acetylgalactosaminyltransferase 2. Angewandte Chemie (International ed. in English), 53(31), 8206-8210. https://doi.org/10.1002/anie.201402781

Substrate-Guided Front-Face Reaction Revealed by Combined Structural Snapshots and Metadynamics for the Polypeptide N-Acetylgalactosaminyltransferase 2. / Lira-Navarrete, Erandi; Iglesias-Fernández, Javier; Zandberg, Wesley F et al.

In: Angewandte Chemie (International ed. in English), Vol. 53, No. 31, 28.07.2014, p. 8206-8210.

Research output: Contribution to journal › Journal article › Research › peer-review

Lira-Navarrete, E, Iglesias-Fernández, J, Zandberg, WF, Compañón, I, Kong, Y, Corzana, F, Pinto, BM, Clausen, H, Peregrina, JM, Vocadlo, DJ, Rovira, C & Hurtado-Guerrero, R 2014, 'Substrate-Guided Front-Face Reaction Revealed by Combined Structural Snapshots and Metadynamics for the Polypeptide N-Acetylgalactosaminyltransferase 2', Angewandte Chemie (International ed. in English), vol. 53, no. 31, pp. 8206-8210. https://doi.org/10.1002/anie.201402781

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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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AU - Zandberg, Wesley F

AU - Compañón, Ismael

AU - Kong, Yun

AU - Corzana, Francisco

AU - Pinto, B Mario

AU - Clausen, Henrik

AU - Peregrina, Jesús M

AU - Vocadlo, David J

AU - Rovira, Carme

AU - Hurtado-Guerrero, Ramon

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N2 - 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.

AB - 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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Substrate-Guided Front-Face Reaction Revealed by Combined Structural Snapshots and Metadynamics for the Polypeptide N-Acetylgalactosaminyltransferase 2

Abstract

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