6h4a | pdb_00006h4a
Human MALT1(329-728) in complex with MLT-748
Structural highlights
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 PubMedMALT1 paracaspase is central for lymphocyte antigen-dependent responses including NF-kappaB activation. We discovered nanomolar, selective allosteric inhibitors of MALT1 that bind by displacing the side chain of Trp580, locking the protease in an inactive conformation. Interestingly, we had previously identified a patient homozygous for a MALT1 Trp580-to-serine mutation who suffered from combined immunodeficiency. We show that the loss of tryptophan weakened interactions between the paracaspase and C-terminal immunoglobulin MALT1 domains resulting in protein instability, reduced protein levels and functions. Upon binding of allosteric inhibitors of increasing potency, we found proportionate increased stabilization of MALT1-W580S to reach that of wild-type MALT1. With restored levels of stable MALT1 protein, the most potent of the allosteric inhibitors rescued NF-kappaB and JNK signaling in patient lymphocytes. Following compound washout, MALT1 substrate cleavage was partly recovered. Thus, a molecular corrector rescues an enzyme deficiency by substituting for the mutated residue, inspiring new potential precision therapies to increase mutant enzyme activity in other deficiencies. An allosteric MALT1 inhibitor is a molecular corrector rescuing function in an immunodeficient patient.,Quancard J, Klein T, Fung SY, Renatus M, Hughes N, Israel L, Priatel JJ, Kang S, Blank MA, Viner RI, Blank J, Schlapbach A, Erbel P, Kizhakkedathu J, Villard F, Hersperger R, Turvey SE, Eder J, Bornancin F, Overall CM Nat Chem Biol. 2019 Jan 28. pii: 10.1038/s41589-018-0222-1. doi:, 10.1038/s41589-018-0222-1. PMID:30692685[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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