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 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Angewandte Chemie (International ed. in English)
Vol/bind	53
Udgave nummer	31
Sider (fra-til)	8206-8210
Antal sider	5
ISSN	1433-7851
DOI	https://doi.org/10.1002/anie.201402781
Status	Udgivet - 28 jul. 2014

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10.1002/anie.201402781

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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.

I: Angewandte Chemie (International ed. in English), Bind 53, Nr. 31, 28.07.2014, s. 8206-8210.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › 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), bind 53, nr. 31, s. 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 - Iglesias-Fernández, Javier

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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