ArticleNature chemical biology2019
An allosteric MALT1 inhibitor is a molecular corrector rescuing function in an immunodeficient patient.
Article in Nature chemical biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 65 citations in OpenAlex.
- Effect of MALT1 inhibition by MI‑2 on the microglial phenotype switch, inflammatory cytokine secretion, neuronal loss and oxidative stress in Alzheimer's disease.International journal of molecular medicine · 2026Article
- A role for the protease MALT1 in EBV-mediated B-cell transformation by Latent Membrane Proteins 1 and 2.Leukemia · 2026Article
- MALT1 protease inhibition restrains glioblastoma progression by reversing tumor-associated macrophage-dependent immunosuppression in mice.Nature communications · 2026Article
- From Dynamics to Diagnosis and Therapy: A Multiscale Computational Framework for MALT1-Targeted Cancer Theranostics.Journal of chemical information and modeling · 2026Article
- Loop dynamics govern MALT1 activation revealed by integrative AlphaFold, MD, and NMR analysis.Scientific reports · 2026Article
- Cereblon induces G3BP2 neosubstrate degradation using molecular surface mimicry.Nature structural & molecular biology · 2026Article
- Therapeutic targeting of MALT1 in oncology: Mechanism, inhibitor development, and clinical prospects.Journal of cell communication and signaling · 2026Review
- Decoding Allosteric Inhibition in MALT1: The Hidden Role of Conformational Plasticity in Metastable States via Biased MD and Deep Learning.The journal of physical chemistry. B · 2026Article
- Insight into Malt1 activation mechanism through synergetic approach of AlphaFold, MD Simulation and NMR dynamic analyses.bioRxiv : the preprint server for biology · 2025Article
- The zymogenic form of SARS-CoV-2 main protease: A discrete target for drug discovery.The Journal of biological chemistry · 2025Article
- Unlocking comprehensive molecular design across all scenarios with large language model and unordered chemical language.Chemical science · 2024Article
- Rational correction of pathogenic conformational defects in HTRA1.Nature communications · 2024Article
- Insights into mechanisms of MALT1 allostery from NMR and AlphaFold dynamic analyses.Communications biology · 2024Article
- Inhibition of MALT1 and BCL2 Induces Synergistic Antitumor Activity in Models of B-Cell Lymphoma.Molecular cancer therapeutics · 2024Article
- Oncogene-induced MALT1 protease activity drives posttranscriptional gene expression in malignant lymphomas.Blood · 2023Article
- Combining precision oncology and immunotherapy by targeting the MALT1 protease.Journal for immunotherapy of cancer · 2022Review
- BCL10 Mutations Define Distinct Dependencies Guiding Precision Therapy for DLBCL.Cancer discovery · 2022Article
- MALT1 Is a Targetable Driver of Epithelial-to-Mesenchymal Transition in Claudin-Low, Triple-Negative Breast Cancer.Molecular cancer research : MCR · 2022Article
- Integrating knowledge of protein sequence with protein function for the prediction and validation of new MALT1 substrates.Computational and structural biotechnology journal · 2022Article
- Progress Identifying and Analyzing the Human Proteome: 2021 Metrics from the HUPO Human Proteome Project.Journal of proteome research · 2021Article
Corrections and comments
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Authors and funding
20 authors at 5 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
MALT1 paracaspase is central for lymphocyte antigen-dependent responses including NF-κB 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-κB 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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.