Structural and functional insight into human O-GlcNAcase

Abstract

O-GlcNAc hydrolase (OGA) removes O-linked N-acetylglucosamine (O-GlcNAc) from a myriad of nucleocytoplasmic proteins. Through co-expression and assembly of OGA fragments, we determined the three-dimensional structure of human OGA, revealing an unusual helix-exchanged dimer that lays a structural foundation for an improved understanding of substrate recognition and regulation of OGA. Structures of OGA in complex with a series of inhibitors define a precise blueprint for the design of inhibitors that have clinical value.

Metadata

Authors/Creators:

Roth, Christian https://orcid.org/0000-0001-5806-0987
Chan, Oi Yi
Offen, Wendy Anne https://orcid.org/0000-0002-2758-4531
Hemsworth, Glyn Robert https://orcid.org/0000-0002-8226-1380
Willems, Lianne Irene https://orcid.org/0000-0001-5411-1329
King, Dustin T.
Varghese, Vimal
Britton, Robert
Vocadlo, David J.
Davies, Gideon John https://orcid.org/0000-0002-7343-776X

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Keywords:

Acetylglucosamine/metabolism, Binding Sites, Enzyme Activation/drug effects, Enzyme Inhibitors/pharmacology, HEK293 Cells, Humans, Ligands, Models, Molecular, Protein Binding, Protein Isoforms/chemistry, Protein Structure, Tertiary, beta-N-Acetylhexosaminidases/chemistry

Dates: