論文 - 詳細
| RRC ID | 54069 |
|---|---|
| 著者 | Nagae M, Kizuka Y, Mihara E, Kitago Y, Hanashima S, Ito Y, Takagi J, Taniguchi N, Yamaguchi Y. |
| タイトル | Structure and mechanism of cancer-associated N-acetylglucosaminyltransferase-V. |
| ジャーナル | 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. |
| 巻・号 | 9(1) |
| ページ | 3380 |
| 公開日 | 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 | 12.121 |
| 引用数 | 12 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 33 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | COS-7(RCB0539) |