7ak1 | pdb_00007ak1

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

spinqualitylabelsall models 7ak1, resolution 2.51Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7ak1 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.507Å Ligands: MG, RJH Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease 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. Function 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. Publication Abstract from PubMed 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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