8cn1

From Proteopedia

(Difference between revisions)

Revision as of 10:36, 2 August 2023

hDLG1-PDZ1 in complex with a TAX1 peptide from HTLV-1

Structural highlights

8cn1 is a 24 chain structure with sequence from Homo sapiens and Human T-cell leukemia virus type I. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.09Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DLG1_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 PubMed

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.

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

↑ Ishidate T, Matsumine A, Toyoshima K, Akiyama T. The APC-hDLG complex negatively regulates cell cycle progression from the G0/G1 to S phase. Oncogene. 2000 Jan 20;19(3):365-72. PMID:10656683 doi:10.1038/sj.onc.1203309
↑ Godreau D, Vranckx R, Maguy A, Rucker-Martin C, Goyenvalle C, Abdelshafy S, Tessier S, Couetil JP, Hatem SN. Expression, regulation and role of the MAGUK protein SAP-97 in human atrial myocardium. Cardiovasc Res. 2002 Dec;56(3):433-42. PMID:12445884
↑ Laprise P, Viel A, Rivard N. Human homolog of disc-large is required for adherens junction assembly and differentiation of human intestinal epithelial cells. J Biol Chem. 2004 Mar 12;279(11):10157-66. Epub 2003 Dec 29. PMID:14699157 doi:10.1074/jbc.M309843200
↑ Xavier R, Rabizadeh S, Ishiguro K, Andre N, Ortiz JB, Wachtel H, Morris DG, Lopez-Ilasaca M, Shaw AC, Swat W, Seed B. Discs large (Dlg1) complexes in lymphocyte activation. J Cell Biol. 2004 Jul 19;166(2):173-8. PMID:15263016 doi:10.1083/jcb.200309044
↑ El-Haou S, Balse E, Neyroud N, Dilanian G, Gavillet B, Abriel H, Coulombe A, Jeromin A, Hatem SN. Kv4 potassium channels form a tripartite complex with the anchoring protein SAP97 and CaMKII in cardiac myocytes. Circ Res. 2009 Mar 27;104(6):758-69. doi: 10.1161/CIRCRESAHA.108.191007. Epub, 2009 Feb 12. PMID:19213956 doi:10.1161/CIRCRESAHA.108.191007
↑ Sabio G, Cerezo-Guisado MI, Del Reino P, Inesta-Vaquera FA, Rousseau S, Arthur JS, Campbell DG, Centeno F, Cuenda A. p38gamma regulates interaction of nuclear PSF and RNA with the tumour-suppressor hDlg in response to osmotic shock. J Cell Sci. 2010 Aug 1;123(Pt 15):2596-604. doi: 10.1242/jcs.066514. Epub 2010, Jul 6. PMID:20605917 doi:10.1242/jcs.066514
↑ 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. Identification of small molecule antivirals against HTLV-1 by targeting the hDLG1-Tax-1 protein-protein interaction. Antiviral Res. 2023 Jul 21;217:105675. PMID:37481039 doi:10.1016/j.antiviral.2023.105675

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8cn1"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8cn1 is ON HOLD  until Paper Publication
+==hDLG1-PDZ1 in complex with a TAX1 peptide from HTLV-1==
+<StructureSection load='8cn1' size='340' side='right'caption='[[8cn1]], [[Resolution|resolution]] 2.09&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8cn1]] is a 24 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Human_T-cell_leukemia_virus_type_I Human T-cell leukemia virus type I]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8CN1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8CN1 FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.09&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8cn1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8cn1 OCA], [https://pdbe.org/8cn1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8cn1 RCSB], [https://www.ebi.ac.uk/pdbsum/8cn1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8cn1 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/DLG1_HUMAN DLG1_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.<ref>PMID:10656683</ref> <ref>PMID:12445884</ref> <ref>PMID:14699157</ref> <ref>PMID:15263016</ref> <ref>PMID:19213956</ref> <ref>PMID:20605917</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+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.
-Authors: Maseko, S., Sogues, A., Volkov, A., Remaut, H., Twizere, J.C.
+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<ref>PMID:37481039</ref>
-Description: hDLG1-PDZ1 in complex with a TAX1 peptide from HTLV-1
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Volkov, A]]
+<div class="pdbe-citations 8cn1" style="background-color:#fffaf0;"></div>
-[[Category: Remaut, H]]
+== References ==
-[[Category: Maseko, S]]
+<references/>
-[[Category: Twizere, J.C]]
+__TOC__
-[[Category: Sogues, A]]
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Human T-cell leukemia virus type I]]
+[[Category: Large Structures]]
+[[Category: Maseko S]]
+[[Category: Remaut H]]
+[[Category: Sogues A]]
+[[Category: Twizere JC]]
+[[Category: Volkov A]]

8cn1

From Proteopedia

Revision as of 10:36, 2 August 2023

hDLG1-PDZ1 in complex with a TAX1 peptide from HTLV-1

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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