9L64
A novel allosteric covalent inhibitory site of fucosyltransferase 8 revealed by crystal structures
This is a non-PDB format compatible entry.
Summary for 9L64
| Entry DOI | 10.2210/pdb9l64/pdb |
| Descriptor | Alpha-(1,6)-fucosyltransferase, 1-hexadecyl-2-methyl-3-(phenylmethyl)imidazol-3-ium (3 entities in total) |
| Functional Keywords | inhibitors, complex, allosteric, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 116072.91 |
| Authors | |
| Primary citation | Jiang, J.,He, D.,Ke, M.,Qin, J.,Yang, G.,Yu, B.,Wang, J.,Fang, P. Exploiting human fucosyltransferase 8 allostery with a covalent inhibitor for core fucosylation suppression. Nat Commun, 2026 Cited by PubMed Abstract: Core fucosylation, catalyzed by fucosyltransferase 8 (FUT8), plays critical roles in cancer progression, immune evasion, and drug resistance, making it a compelling therapeutic target. However, development of selective FUT8 inhibitors has been hindered by shared substrate specificity of fucosyltransferases. Here, we report the discovery of a previously unrecognized allosteric site on FUT8 and the development of a low-toxicity covalent inhibitor, CAIF (stearic acid-N-hydroxysuccinimide ester-dimethylimidazolium bromide), through structure-based drug design. High-throughput screening and crystallographic studies reveal that small molecules such as NH125 bind to a channel-like allosteric pocket, inducing conformational changes that disrupt FUT8 activity. Leveraging these insights, we design CAIF to covalently target lysine K216 within the allosteric site. CAIF exhibits minimal cytotoxicity and significantly inhibits core fucosylation and cancer cell invasion in cellular assays. This work establishes CAIF as a lead compound for further optimization and development, offering a framework for targeting glycosyltransferases through allosteric and covalent inhibition strategies. PubMed: 41667477DOI: 10.1038/s41467-026-68971-7 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.49 Å) |
Structure validation
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