7ak0

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==Human MALT1(329-729) in complex with a chromane urea containing inhibitor==
==Human MALT1(329-729) in complex with a chromane urea containing inhibitor==
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<StructureSection load='7ak0' size='340' side='right'caption='[[7ak0]]' scene=''>
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<StructureSection load='7ak0' size='340' side='right'caption='[[7ak0]], [[Resolution|resolution]] 2.32&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AK0 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7AK0 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[7ak0]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AK0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AK0 FirstGlance]. <br>
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</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=7ak0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ak0 OCA], [http://pdbe.org/7ak0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7ak0 RCSB], [http://www.ebi.ac.uk/pdbsum/7ak0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7ak0 ProSAT]</span></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.316&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=RJK:1-[4-[4-(aminomethyl)pyrazol-1-yl]-3-chloranyl-phenyl]-3-[(3~{R})-6-bromanyl-3,4-dihydro-2~{H}-chromen-3-yl]urea'>RJK</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7ak0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ak0 OCA], [https://pdbe.org/7ak0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ak0 RCSB], [https://www.ebi.ac.uk/pdbsum/7ak0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ak0 ProSAT]</span></td></tr>
</table>
</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/MALT1_HUMAN MALT1_HUMAN] Note=A chromosomal aberration involving MALT1 is recurrent in low-grade mucosa-associated lymphoid tissue (MALT lymphoma). Translocation t(11;18)(q21;q21) with BIRC2. This translocation is found in approximately 50% of cytogenetically abnormal low-grade MALT lymphoma.
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== Function ==
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[https://www.uniprot.org/uniprot/MALT1_HUMAN MALT1_HUMAN] Enhances BCL10-induced activation of NF-kappa-B. Involved in nuclear export of BCL10. Binds to TRAF6, inducing TRAF6 oligomerization and activation of its ligase activity. Has ubiquitin ligase activity. MALT1-dependent BCL10 cleavage plays an important role in T-cell antigen receptor-induced integrin adhesion.<ref>PMID:11262391</ref> <ref>PMID:14695475</ref> <ref>PMID:18264101</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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MALT1 plays a central role in immune cell activation by transducing NF-kappaB signaling, and its proteolytic activity represents a key node for therapeutic intervention. Two cycles of scaffold morphing of a high-throughput biochemical screening hit resulted in the discovery of MLT-231, which enabled the successful pharmacological validation of MALT1 allosteric inhibition in preclinical models of humoral immune responses and B-cell lymphomas. Herein, we report the structural activity relationships (SARs) and analysis of the physicochemical properties of a pyrazolopyrimidine-derived compound series. In human T-cells and B-cell lymphoma lines, MLT-231 potently and selectively inhibits the proteolytic activity of MALT1 in NF-kappaB-dependent assays. Both in vitro and in vivo profiling of MLT-231 support further optimization of this in vivo tool compound toward preclinical characterization.
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Discovery of Potent, Highly Selective, and In Vivo Efficacious, Allosteric MALT1 Inhibitors by Iterative Scaffold Morphing.,Pissot Soldermann C, Simic O, Renatus M, Erbel P, Melkko S, Wartmann M, Bigaud M, Weiss A, McSheehy P, Endres R, Santos P, Blank J, Schuffenhauer A, Bold G, Buschmann N, Zoller T, Altmann E, Manley PW, Dix I, Buchdunger E, Scesa J, Quancard J, Schlapbach A, Bornancin F, Radimerski T, Regnier CH J Med Chem. 2020 Nov 30. doi: 10.1021/acs.jmedchem.0c01245. PMID:33252239<ref>PMID:33252239</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 7ak0" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Renatus M]]
[[Category: Renatus M]]

Current revision

Human MALT1(329-729) in complex with a chromane urea containing inhibitor

PDB ID 7ak0

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