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5joh

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Revision as of 11:31, 17 June 2020

CRYSTAL STRUCTURE OF CSN5(2-257) IN COMPLEX WITH CNS5i-1b

Structural highlights

5joh is a 1 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:	COPS5, CSN5, JAB1 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[CSN5_HUMAN] Probable protease subunit of the COP9 signalosome complex (CSN), a complex involved in various cellular and developmental processes. The CSN complex is an essential regulator of the ubiquitin (Ubl) conjugation pathway by mediating the deneddylation of the cullin subunits of the SCF-type E3 ligase complexes, leading to decrease the Ubl ligase activity of SCF-type complexes such as SCF, CSA or DDB2. The complex is also involved in phosphorylation of p53/TP53, c-jun/JUN, IkappaBalpha/NFKBIA, ITPK1 and IRF8, possibly via its association with CK2 and PKD kinases. CSN-dependent phosphorylation of TP53 and JUN promotes and protects degradation by the Ubl system, respectively. In the complex, it probably acts as the catalytic center that mediates the cleavage of Nedd8 from cullins. It however has no metalloprotease activity by itself and requires the other subunits of the CSN complex. Interacts directly with a large number of proteins that are regulated by the CSN complex, confirming a key role in the complex. Promotes the proteasomal degradation of BRSK2.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7]

Publication Abstract from PubMed

The COP9 signalosome (CSN) is a central component of the activation and remodelling cycle of cullin-RING E3 ubiquitin ligases (CRLs), the largest enzyme family of the ubiquitin-proteasome system in humans. CRLs are implicated in the regulation of numerous cellular processes, including cell cycle progression and apoptosis, and aberrant CRL activity is frequently associated with cancer. Remodelling of CRLs is initiated by CSN-catalysed cleavage of the ubiquitin-like activator NEDD8 from CRLs. Here we describe CSN5i-3, a potent, selective and orally available inhibitor of CSN5, the proteolytic subunit of CSN. The compound traps CRLs in the neddylated state, which leads to inactivation of a subset of CRLs by inducing degradation of their substrate recognition module. CSN5i-3 differentially affects the viability of tumour cell lines and suppresses growth of a human xenograft in mice. Our results provide insights into how CSN regulates CRLs and suggest that CSN5 inhibition has potential for anti-tumour therapy.

Targeted inhibition of the COP9 signalosome for treatment of cancer.,Schlierf A, Altmann E, Quancard J, Jefferson AB, Assenberg R, Renatus M, Jones M, Hassiepen U, Schaefer M, Kiffe M, Weiss A, Wiesmann C, Sedrani R, Eder J, Martoglio B Nat Commun. 2016 Oct 24;7:13166. doi: 10.1038/ncomms13166. PMID:27774986^[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Seeger M, Kraft R, Ferrell K, Bech-Otschir D, Dumdey R, Schade R, Gordon C, Naumann M, Dubiel W. A novel protein complex involved in signal transduction possessing similarities to 26S proteasome subunits. FASEB J. 1998 Apr;12(6):469-78. PMID:9535219
↑ Bech-Otschir D, Kraft R, Huang X, Henklein P, Kapelari B, Pollmann C, Dubiel W. COP9 signalosome-specific phosphorylation targets p53 to degradation by the ubiquitin system. EMBO J. 2001 Apr 2;20(7):1630-9. PMID:11285227 doi:http://dx.doi.org/10.1093/emboj/20.7.1630
↑ Lyapina S, Cope G, Shevchenko A, Serino G, Tsuge T, Zhou C, Wolf DA, Wei N, Shevchenko A, Deshaies RJ. Promotion of NEDD-CUL1 conjugate cleavage by COP9 signalosome. Science. 2001 May 18;292(5520):1382-5. Epub 2001 May 3. PMID:11337588 doi:http://dx.doi.org/10.1126/science.1059780
↑ Groisman R, Polanowska J, Kuraoka I, Sawada J, Saijo M, Drapkin R, Kisselev AF, Tanaka K, Nakatani Y. The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage. Cell. 2003 May 2;113(3):357-67. PMID:12732143
↑ Uhle S, Medalia O, Waldron R, Dumdey R, Henklein P, Bech-Otschir D, Huang X, Berse M, Sperling J, Schade R, Dubiel W. Protein kinase CK2 and protein kinase D are associated with the COP9 signalosome. EMBO J. 2003 Mar 17;22(6):1302-12. PMID:12628923 doi:http://dx.doi.org/10.1093/emboj/cdg127
↑ Cooper EM, Cutcliffe C, Kristiansen TZ, Pandey A, Pickart CM, Cohen RE. K63-specific deubiquitination by two JAMM/MPN+ complexes: BRISC-associated Brcc36 and proteasomal Poh1. EMBO J. 2009 Mar 18;28(6):621-31. doi: 10.1038/emboj.2009.27. Epub 2009 Feb 12. PMID:19214193 doi:http://dx.doi.org/10.1038/emboj.2009.27
↑ Zhou J, Wan B, Li R, Gu X, Zhong Z, Wang Y, Yu L. Jab1 interacts with brain-specific kinase 2 (BRSK2) and promotes its degradation in the ubiquitin-proteasome pathway. Biochem Biophys Res Commun. 2012 Jun 15;422(4):647-52. doi:, 10.1016/j.bbrc.2012.05.045. Epub 2012 May 16. PMID:22609399 doi:http://dx.doi.org/10.1016/j.bbrc.2012.05.045
↑ Schlierf A, Altmann E, Quancard J, Jefferson AB, Assenberg R, Renatus M, Jones M, Hassiepen U, Schaefer M, Kiffe M, Weiss A, Wiesmann C, Sedrani R, Eder J, Martoglio B. Targeted inhibition of the COP9 signalosome for treatment of cancer. Nat Commun. 2016 Oct 24;7:13166. doi: 10.1038/ncomms13166. PMID:27774986 doi:http://dx.doi.org/10.1038/ncomms13166

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5joh"

@@ Line 1: / Line 1: @@
 ==CRYSTAL STRUCTURE OF CSN5(2-257) IN COMPLEX WITH CNS5i-1b==
-<StructureSection load='5joh' size='340' side='right' caption='[[5joh]], [[Resolution|resolution]] 1.99&Aring;' scene=''>
+<StructureSection load='5joh' size='340' side='right'caption='[[5joh]], [[Resolution|resolution]] 1.99&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5joh]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5JOH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5JOH FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5joh]] is a 1 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=5JOH OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5JOH FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6M3:2-CHLORO-6-[(5S,6S)-6-HYDROXY-6,7,8,9-TETRAHYDRO-5H-IMIDAZO[1,5-A]AZEPIN-5-YL][1,1-BIPHENYL]-3-CARBONITRILE'>6M3</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6M3:2-CHLORO-6-[(5S,6S)-6-HYDROXY-6,7,8,9-TETRAHYDRO-5H-IMIDAZO[1,5-A]AZEPIN-5-YL][1,1-BIPHENYL]-3-CARBONITRILE'>6M3</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=5joh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5joh OCA], [http://pdbe.org/5joh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5joh RCSB], [http://www.ebi.ac.uk/pdbsum/5joh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5joh ProSAT]</span></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">COPS5, CSN5, JAB1 ([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://proteopedia.org/fgij/fg.htm?mol=5joh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5joh OCA], [http://pdbe.org/5joh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5joh RCSB], [http://www.ebi.ac.uk/pdbsum/5joh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5joh ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 19: @@
 </div>
 <div class="pdbe-citations 5joh" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Signalosome|Signalosome]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Renatus, M]]
 [[Category: Wiesmann, C]]

5joh

From Proteopedia

Revision as of 11:31, 17 June 2020

CRYSTAL STRUCTURE OF CSN5(2-257) IN COMPLEX WITH CNS5i-1b

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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