6F7I

human MALT1(329-728) IN COMPLEX WITH MLT-747

Summary for 6F7I

• Entry DOI: 10.2210/pdb6f7i/pdb
• Descriptor: Mucosa-associated lymphoid tissue lymphoma translocation protein 1, 1-[2-chloranyl-7-[(1~{S})-1-methoxyethyl]pyrazolo[1,5-a]pyrimidin-6-yl]-3-(5-chloranyl-6-pyrrolidin-1-ylcarbonyl-pyridin-3-yl)urea, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: dimer, exosite binder, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 92548.23

Authors

Renatus, M.,Renatus, M. (deposition date: 2017-12-09, release date: 2019-01-02, Last modification date: 2024-05-01)

Primary citation

Quancard, J.,Klein, T.,Fung, S.Y.,Renatus, M.,Hughes, N.,Israel, L.,Priatel, J.J.,Kang, S.,Blank, M.A.,Viner, R.I.,Blank, J.,Schlapbach, A.,Erbel, P.,Kizhakkedathu, J.,Villard, F.,Hersperger, R.,Turvey, S.E.,Eder, J.,Bornancin, F.,Overall, C.M.
An allosteric MALT1 inhibitor is a molecular corrector rescuing function in an immunodeficient patient.
Nat. Chem. Biol., 15:304-313, 2019

PubMed 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.

PubMed: 30692685
DOI: 10.1038/s41589-018-0222-1

Experimental method

X-RAY DIFFRACTION (2.43 Å)