8v4x

From Proteopedia

Structure of MALT1 in complex with an allosteric inhibitor

Structural highlights

8v4x is a 12 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.486Å
Ligands:	, ,
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.^[1] ^[2] ^[3]

Publication Abstract from PubMed

The activated B cell (ABC) subset of diffuse large B-cell lymphoma (DLBCL) is characterized by chronic B-cell receptor signaling and associated with poor outcomes when treated with standard therapy. In ABC-DLBCL, MALT1 is a core enzyme that is constitutively activated by stimulation of the B-cell receptor or gain-of-function mutations in upstream components of the signaling pathway, making it an attractive therapeutic target. We discovered a novel small-molecule inhibitor, ABBV-MALT1, that potently shuts down B-cell signaling selectively in ABC-DLBCL preclinical models leading to potent cell growth and xenograft inhibition. We also identified a rational combination partner for ABBV-MALT1 in the BCL2 inhibitor, venetoclax, which when combined significantly synergizes to elicit deep and durable responses in preclinical models. This work highlights the potential of ABBV-MALT1 monotherapy and combination with venetoclax as effective treatment options for patients with ABC-DLBCL.

Inhibition of MALT1 and BCL2 Induces Synergistic Antitumor Activity in Models of B-Cell Lymphoma.,Plotnik JP, Richardson AE, Yang H, Rojas E, Bontcheva V, Dowell C, Parsons S, Wilson A, Ravanmehr V, Will C, Jung P, Zhu H, Partha SK, Panchal SC, Mali RS, Kohlhapp FJ, McClure RA, Ramathal CY, George MD, Jhala M, Elsen NL, Qiu W, Judge RA, Pan C, Mastracchio A, Henderson J, Meulbroek JA, Green MR, Pappano WN Mol Cancer Ther. 2024 Jul 2;23(7):949-960. doi: 10.1158/1535-7163.MCT-23-0518. PMID:38507740^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lucas PC, Yonezumi M, Inohara N, McAllister-Lucas LM, Abazeed ME, Chen FF, Yamaoka S, Seto M, Nunez G. Bcl10 and MALT1, independent targets of chromosomal translocation in malt lymphoma, cooperate in a novel NF-kappa B signaling pathway. J Biol Chem. 2001 Jun 1;276(22):19012-9. Epub 2001 Mar 21. PMID:11262391 doi:10.1074/jbc.M009984200
↑ Zhou H, Wertz I, O'Rourke K, Ultsch M, Seshagiri S, Eby M, Xiao W, Dixit VM. Bcl10 activates the NF-kappaB pathway through ubiquitination of NEMO. Nature. 2004 Jan 8;427(6970):167-71. Epub 2003 Dec 24. PMID:14695475 doi:10.1038/nature02273
↑ Rebeaud F, Hailfinger S, Posevitz-Fejfar A, Tapernoux M, Moser R, Rueda D, Gaide O, Guzzardi M, Iancu EM, Rufer N, Fasel N, Thome M. The proteolytic activity of the paracaspase MALT1 is key in T cell activation. Nat Immunol. 2008 Mar;9(3):272-81. doi: 10.1038/ni1568. Epub 2008 Feb 10. PMID:18264101 doi:10.1038/ni1568
↑ Plotnik JP, Richardson AE, Yang H, Rojas E, Bontcheva V, Dowell C, Parsons S, Wilson A, Ravanmehr V, Will C, Jung P, Zhu H, Partha SK, Panchal SC, Mali RS, Kohlhapp FJ, McClure RA, Ramathal CY, George MD, Jhala M, Elsen NL, Qiu W, Judge RA, Pan C, Mastracchio A, Henderson J, Meulbroek JA, Green MR, Pappano WN. Inhibition of MALT1 and BCL2 Induces Synergistic Antitumor Activity in Models of B-Cell Lymphoma. Mol Cancer Ther. 2024 Jul 2;23(7):949-960. PMID:38507740 doi:10.1158/1535-7163.MCT-23-0518