2. Academic Validation
  3. Structure and mechanism of cancer-associated N-acetylglucosaminyltransferase-V

Structure and mechanism of cancer-associated N-acetylglucosaminyltransferase-V

  • Nat Commun. 2018 Aug 23;9(1):3380. doi: 10.1038/s41467-018-05931-w.
Masamichi Nagae 1 2,  Yasuhiko Kizuka 3 4,  Emiko Mihara 5,  Yu Kitago 5,  Shinya Hanashima 6,  Yukishige Ito 7,  Junichi Takagi 5,  Naoyuki Taniguchi 3,  Yoshiki Yamaguchi 8
Affiliations

Affiliations

  • 1 Structural Glycobiology Team, Glycobiology Research Group, Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan. [email protected].
  • 2 Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-0033, Japan. [email protected].
  • 3 Disease Glycomics Team, Systems Glycobiology Research Group, Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
  • 4 Center for Highly Advanced Integration of Nano and Life Sciences (G-CHAIN), Gifu University, 1-1 Yanagido, Gifu-City, Gifu, 501-1193, Japan.
  • 5 Institute for Protein Research, Osaka University, Suita, Osaka, 565-0871, Japan.
  • 6 Department of Chemistry, Osaka University, Machikaneyama, Toyonaka, Osaka, 560-0043, Japan.
  • 7 Synthetic Cellular Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
  • 8 Structural Glycobiology Team, Glycobiology Research Group, Global Research Cluster, RIKEN, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
PMID: 30140003 DOI: 10.1038/s41467-018-05931-w
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.

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