RRC ID 54069
Author Nagae M, Kizuka Y, Mihara E, Kitago Y, Hanashima S, Ito Y, Takagi J, Taniguchi N, Yamaguchi Y.
Title Structure and mechanism of cancer-associated N-acetylglucosaminyltransferase-V.
Journal Nat Commun
Abstract N-acetylglucosaminyltransferase-V (GnT-V) alters the structure of specific N-glycans by modifying α1-6-linked mannose with a β1-6-linked N-acetylglucosamine branch. β1-6 branch formation on cell surface receptors accelerates cancer metastasis, making GnT-V a promising target for drug development. However, the molecular basis of GnT-V's catalytic mechanism and substrate specificity are not fully understood. Here, we report crystal structures of human GnT-V luminal domain with a substrate analog. GnT-V luminal domain is composed of a GT-B fold and two accessary domains. Interestingly, two aromatic rings sandwich the α1-6 branch of the acceptor N-glycan and restrain the global conformation, partly explaining the fine branch specificity of GnT-V. In addition, interaction of the substrate N-glycoprotein with GnT-V likely contributes to protein-selective and site-specific glycan modification. In summary, the acceptor-GnT-V complex structure suggests a catalytic mechanism, explains the previously observed inhibition of GnT-V by branching enzyme GnT-III, and provides a basis for the rational design of drugs targeting N-glycan branching.
Volume 9(1)
Pages 3380
Published 2018-8-23
DOI 10.1038/s41467-018-05931-w
PII 10.1038/s41467-018-05931-w
PMID 30140003
PMC PMC6107550
MeSH Antineoplastic Agents / pharmacology Antineoplastic Agents / therapeutic use Biocatalysis Catalytic Domain / physiology* Crystallography, X-Ray Drug Design Enzyme Assays Glycoproteins / chemistry Glycoproteins / metabolism Humans Molecular Docking Simulation Mutagenesis, Site-Directed N-Acetylglucosaminyltransferases / antagonists & inhibitors N-Acetylglucosaminyltransferases / chemistry N-Acetylglucosaminyltransferases / genetics N-Acetylglucosaminyltransferases / metabolism* Neoplasms / drug therapy Neoplasms / pathology* Polysaccharides / chemistry Polysaccharides / metabolism* Substrate Specificity
IF 11.878
Times Cited 12
Resource
Human and Animal Cells COS-7(RCB0539)