9mkd | pdb_00009mkd

Crystal structure of MALT1 in complex with an allosteric inhibitor

spinqualitylabelsall models 9mkd, resolution 2.45Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9mkd is a 2 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 2.45Å Ligands: A1BMX, CA, PGE 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 is a key component of the CARD11-BCL10-MALT1 (CBM) complex downstream from BTK on the B-cell receptor signaling pathway. It is a key mediator of NF-kappaB signaling and considered a potential therapeutic target for several subtypes of non-Hodgkin's B-cell lymphomas. By applying advanced physics-based modeling techniques, including combining free energy calculations with machine learning methods and a chemistry-aware compound enumeration workflow, extensive sets of de novo design ideas were explored to quickly identify a novel hit series. Multiparameter optimization allowed efficient prioritization of molecules with good potency and drug-like properties during lead optimization, which led to the discovery of a highly potent MALT1 inhibitor, SGR-1505, with a well-balanced property profile. It demonstrated strong antitumor activity alone and in combination with BTK inhibitor in multiple in vivo B-cell lymphoma xenograft models and progressed to a phase 1 clinical trial in patients with mature B-cell neoplasms. Accelerated In Silico Discovery of SGR-1505: A Potent MALT1 Allosteric Inhibitor for the Treatment of Mature B-Cell Malignancies.,Nie Z, Trzoss M, Placzek AT, Trzoss L, Krilov G, Feng S, Lawrenz M, Ye M, Marshall N, Dingley KH, Pelletier RD, Lai WG, Bell JA, Tang H, Devine P, Liu Z, Skrdla P, Shimanovich R, Liu M, Wang R, Xu X, Abel R, Akinsanya K, Yin W J Med Chem. 2025 Oct 13. doi: 10.1021/acs.jmedchem.5c01494. PMID:41078320 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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