6f7i

From Proteopedia

(Difference between revisions)

Revision as of 09:47, 13 February 2019

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

Structural highlights

6f7i is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Gene:	MALT1, MLT (HUMAN)
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 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

↑ 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
↑ 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. An allosteric MALT1 inhibitor is a molecular corrector rescuing function in an immunodeficient patient. Nat Chem Biol. 2019 Jan 28. pii: 10.1038/s41589-018-0222-1. doi:, 10.1038/s41589-018-0222-1. PMID:30692685 doi:http://dx.doi.org/10.1038/s41589-018-0222-1

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/6f7i"

Categories: Human | Renatus, M | Dimer | Exosite binder | Hydrolase

@@ Line 3: / Line 3: @@
 <StructureSection load='6f7i' size='340' side='right' caption='[[6f7i]], [[Resolution|resolution]] 2.43&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6f7i]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6F7I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6F7I FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6f7i]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6F7I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6F7I FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CW5:1-[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'>CW5</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MALT1, MLT ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6f7i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6f7i OCA], [http://pdbe.org/6f7i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6f7i RCSB], [http://www.ebi.ac.uk/pdbsum/6f7i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6f7i ProSAT]</span></td></tr>
 </table>
@@ Line 11: / Line 12: @@
 == Function ==
 [[http://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 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<ref>PMID:30692685</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6f7i" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Renatus, M]]
 [[Category: Dimer]]
 [[Category: Exosite binder]]
 [[Category: Hydrolase]]

6f7i

From Proteopedia

Revision as of 09:47, 13 February 2019

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

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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