9mkd

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of MALT1 in complex with an allosteric inhibitor

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:	, ,
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

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^[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
↑ 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. Accelerated In Silico Discovery of SGR-1505: A Potent MALT1 Allosteric Inhibitor for the Treatment of Mature B-Cell Malignancies. J Med Chem. 2025 Oct 13. PMID:41078320 doi:10.1021/acs.jmedchem.5c01494

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/9mkd"

Categories: Homo sapiens | Large Structures | Bell JA

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9mkd is ON HOLD  until Paper Publication
+==Crystal structure of MALT1 in complex with an allosteric inhibitor==
+<StructureSection load='9mkd' size='340' side='right'caption='[[9mkd]], [[Resolution|resolution]] 2.45&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9mkd]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9MKD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9MKD FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.45&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1BMX:(9R)-2-chloro-N-[5-chloro-6-(2H-1,2,3-triazol-2-yl)pyridin-3-yl]-8,8-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[2,3-e]pyrimidine-6-carboxamide'>A1BMX</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9mkd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9mkd OCA], [https://pdbe.org/9mkd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9mkd RCSB], [https://www.ebi.ac.uk/pdbsum/9mkd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9mkd ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/MALT1_HUMAN 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 ==
+[https://www.uniprot.org/uniprot/MALT1_HUMAN 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.<ref>PMID:11262391</ref> <ref>PMID:14695475</ref> <ref>PMID:18264101</ref>
+<div style="background-color:#fffaf0;">
+== 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.
-Authors: Bell, J.A.
+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<ref>PMID:41078320</ref>
-Description: Crystal structure of MALT1 in complex with an allosteric inhibitor
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Bell, J.A]]
+<div class="pdbe-citations 9mkd" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Bell JA]]

9mkd

From Proteopedia

Current revision

Crystal structure of MALT1 in complex with an allosteric inhibitor

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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