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Substrate engagement and catalytic mechanisms of N-acetylglucosaminyltransferase V

DOI: 10.1021/acscatal.0c02222 DOI Help

Authors: John F. Darby (University of York) , Amelia K. Gilio (University of York) , Beatriz Piniello (Universitat de Barcelona) , Christian Roth (University of York) , Elena Blagova (University of York) , Roderick E. Hubbard (University of York) , Carme Rovira (Universitat de Barcelona; Institució Catalana de Recerca i Estudis Avançats (ICREA)) , Gideon J. Davies (University of York) , Liang Wu (University of York)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Catalysis

State: Published (Approved)
Published: July 2020
Diamond Proposal Number(s): 18598

Open Access Open Access

Abstract: α-mannoside β-1,6-N-acetylglucosaminyltransferase V (MGAT5) is a mammalian glycosyltransferase involved in complex N-glycan formation, which strongly drives cancer when overexpressed. Despite intense interest, the catalytic mechanism of MGAT5 is not known in detail, precluding therapeutic exploitation. We solved structures of MGAT5 complexed to glycosyl donor and acceptor ligands, revealing an unforeseen role for donor induced loop rearrangements in controlling acceptor substrate engagement. QM/MM metadynamics simulations of MGAT5 catalysis highlight the key assisting role of Glu297, and reveal considerable conformational distortions imposed upon the glycosyl donor during transfer. Detailed mechanistic characterization of MGAT5 will aid inhibitor development to correct cancer associated N-glycosylation.

Journal Keywords: Enzymes; N-glycosylation; Carbohydrates; Glycosyltransferases; Quantum mechanics/Molecular mechanics

Diamond Keywords: Enzymes

Subject Areas: Chemistry, Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 20/07/2020 09:35


Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Catalysis Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)