8cn1
From Proteopedia
hDLG1-PDZ1 in complex with a TAX1 peptide from HTLV-1
Structural highlights
FunctionDLG1_HUMAN Essential multidomain scaffolding protein required for normal development (By similarity). Recruits channels, receptors and signaling molecules to discrete plasma membrane domains in polarized cells. May play a role in adherens junction assembly, signal transduction, cell proliferation, synaptogenesis and lymphocyte activation. Regulates the excitability of cardiac myocytes by modulating the functional expression of Kv4 channels. Functional regulator of Kv1.5 channel.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedHuman 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. Identification of small molecule antivirals against HTLV-1 by targeting the hDLG1-Tax-1 protein-protein interaction.,Maseko SB, 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 AN, Twizere JC Antiviral Res. 2023 Jul 21;217:105675. doi: 10.1016/j.antiviral.2023.105675. PMID:37481039[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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