8CN3

hDLG1-PDZ2 in complex with a TAX1 peptide from HTLV-1

8CN3 の概要

• エントリーDOI: 10.2210/pdb8cn3/pdb
• 分子名称: Disks large homolog 1, GLU-THR-GLU-VAL, ... (4 entities in total)
• 機能のキーワード: htlv-1; tax-1; hdlg1; pbm, protein protein interaction, protein binding
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 25717.33

構造登録者

Maseko, S.,Sogues, A.,Volkov, A.,Remaut, H.,Twizere, J.C. (登録日: 2023-02-21, 公開日: 2023-08-02, 最終更新日: 2024-06-19)

主引用文献

Maseko, S.B.,Brammerloo, Y.,Van Molle, I.,Sogues, A.,Martin, C.,Gorgulla, C.,Plant, E.,Olivet, J.,Blavier, J.,Ntombela, T.,Delvigne, F.,Arthanari, H.,El Hajj, H.,Bazarbachi, A.,Van Lint, C.,Salehi-Ashtiani, K.,Remaut, H.,Ballet, S.,Volkov, A.N.,Twizere, J.C.
Identification of small molecule antivirals against HTLV-1 by targeting the hDLG1-Tax-1 protein-protein interaction.
Antiviral Res., 217:105675-105675, 2023

PubMed Abstract: Human T-cell leukemia virus type-1 (HTLV-1) is the first pathogenic retrovirus discovered in human. Although HTLV-1-induced diseases are well-characterized and linked to the encoded Tax-1 oncoprotein, there is currently no strategy to target Tax-1 functions with small molecules. Here, we analyzed the binding of Tax-1 to the human homolog of the drosophila discs large tumor suppressor (hDLG1/SAP97), a multi-domain scaffolding protein involved in Tax-1-transformation ability. We have solved the structures of the PDZ binding motif (PBM) of Tax-1 in complex with the PDZ1 and PDZ2 domains of hDLG1 and assessed the binding of 10 million molecules by virtual screening. Among the 19 experimentally confirmed compounds, one systematically inhibited the Tax-1-hDLG1 interaction in different biophysical and cellular assays, as well as HTLV-1 cell-to-cell transmission in a T-cell model. Thus, our work demonstrates that interactions involving Tax-1 PDZ-domains are amenable to small-molecule inhibition, which provides a framework for the design of targeted therapies for HTLV-1-induced diseases.

PubMed: 37481039
DOI: 10.1016/j.antiviral.2023.105675

実験手法

X-RAY DIFFRACTION (2.71 Å)