8CN3

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

Summary for 8CN3

• Entry DOI: 10.2210/pdb8cn3/pdb
• Descriptor: Disks large homolog 1, GLU-THR-GLU-VAL, ... (4 entities in total)
• Functional Keywords: htlv-1; tax-1; hdlg1; pbm, protein protein interaction, protein binding
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 25717.33

Authors

Maseko, S.,Sogues, A.,Volkov, A.,Remaut, H.,Twizere, J.C. (deposition date: 2023-02-21, release date: 2023-08-02, Last modification date: 2024-06-19)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.71 Å)