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5xu8

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Revision as of 06:58, 14 October 2020

Crystal structure of human USP2 in complex with ubiquitin and 6-thioguanine

Structural highlights

5xu8 is a 2 chain structure with sequence from [1] and Bos taurus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
Activity:	Ubiquitinyl hydrolase 1, with EC number 3.4.19.12
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[UBP2_HUMAN] Hydrolase that deubiquitinates polyubiquitinated target proteins such as MDM2, MDM4 and CCND1. Isoform 1 and isoform 4 possess both ubiquitin-specific peptidase and isopeptidase activities. Deubiquitinates MDM2 without reversing MDM2-mediated p53/TP53 ubiquitination and thus indirectly promotes p53/TP53 degradation and limits p53 activity. Has no deubiquitinase activity against p53/TP53. Prevents MDM2-mediated degradation of MDM4. Plays a role in the G1/S cell-cycle progression in normal and cancer cells. Plays a role in the regulation of myogenic differentiation of embryonic muscle cells.^[1] ^[2] ^[3] [RS27A_BOVIN] Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling (By similarity). Ribosomal protein S27a is a component of the 40S subunit of the ribosome.

Publication Abstract from PubMed

Ubiquitin-specific protease 2 (USP2) belongs to the family of deubiquitinases that can rescue protein targets from proteasomal degradation by reversing their ubiquitination. In various cancers, including prostate cancer and ovarian carcinoma, upregulation of USP2 leads to an increase in the levels of deubiquitinated substrates such as fatty acid synthase, MDM2, cyclin D1 and Aurora-A. USP2 thus plays a critical role in tumor cells' survival and therefore represents a therapeutic target. Here a leukemia drug, 6-thioguanine, was found to be a potent inhibitor of USP2. Enzyme-kinetic and X-ray crystallographic data suggest that 6-thioguanine displays a noncompetitive and slow-binding inhibitory mechanism against USP2. Our study provides a clear rationale for the clinical evaluation of 6-thioguanine for USP2-upregulated cancers.

6-Thioguanine is a noncompetitive and slow binding inhibitor of human deubiquitinating protease USP2.,Chuang SJ, Cheng SC, Tang HC, Sun CY, Chou CY Sci Rep. 2018 Feb 15;8(1):3102. doi: 10.1038/s41598-018-21476-w. PMID:29449607^[4]

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

References

↑ Stevenson LF, Sparks A, Allende-Vega N, Xirodimas DP, Lane DP, Saville MK. The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2. EMBO J. 2007 Feb 21;26(4):976-86. Epub 2007 Feb 8. PMID:17290220 doi:10.1038/sj.emboj.7601567
↑ Shan J, Zhao W, Gu W. Suppression of cancer cell growth by promoting cyclin D1 degradation. Mol Cell. 2009 Nov 13;36(3):469-76. doi: 10.1016/j.molcel.2009.10.018. PMID:19917254 doi:10.1016/j.molcel.2009.10.018
↑ Allende-Vega N, Sparks A, Lane DP, Saville MK. MdmX is a substrate for the deubiquitinating enzyme USP2a. Oncogene. 2010 Jan 21;29(3):432-41. doi: 10.1038/onc.2009.330. Epub 2009 Oct 19. PMID:19838211 doi:10.1038/onc.2009.330
↑ Chuang SJ, Cheng SC, Tang HC, Sun CY, Chou CY. 6-Thioguanine is a noncompetitive and slow binding inhibitor of human deubiquitinating protease USP2. Sci Rep. 2018 Feb 15;8(1):3102. doi: 10.1038/s41598-018-21476-w. PMID:29449607 doi:http://dx.doi.org/10.1038/s41598-018-21476-w

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/5xu8"

@@ Line 1: / Line 1: @@
 ==Crystal structure of human USP2 in complex with ubiquitin and 6-thioguanine==
-<StructureSection load='5xu8' size='340' side='right' caption='[[5xu8]], [[Resolution|resolution]] 1.81&Aring;' scene=''>
+<StructureSection load='5xu8' size='340' side='right'caption='[[5xu8]], [[Resolution|resolution]] 1.81&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5xu8]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/ ] and [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5XU8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5XU8 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5xu8]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/ ] and [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5XU8 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5XU8 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DX4:2-AMINO-1,9-DIHYDRO-6H-PURINE-6-THIONE'>DX4</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DX4:2-AMINO-1,9-DIHYDRO-6H-PURINE-6-THIONE'>DX4</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Ubiquitinyl_hydrolase_1 Ubiquitinyl hydrolase 1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.19.12 3.4.19.12] </span></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=5xu8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xu8 OCA], [http://pdbe.org/5xu8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5xu8 RCSB], [http://www.ebi.ac.uk/pdbsum/5xu8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5xu8 ProSAT]</span></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=5xu8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xu8 OCA], [http://pdbe.org/5xu8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5xu8 RCSB], [http://www.ebi.ac.uk/pdbsum/5xu8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5xu8 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 19: / Line 19: @@
 </div>
 <div class="pdbe-citations 5xu8" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Thioesterase 3D structures|Thioesterase 3D structures]]
 == References ==
 <references/>
@@ Line 24: / Line 27: @@
 </StructureSection>
 [[Category: Bos taurus]]
+[[Category: Large Structures]]
 [[Category: Ubiquitinyl hydrolase 1]]
 [[Category: Chou, C Y]]

5xu8

From Proteopedia

Revision as of 06:58, 14 October 2020

Crystal structure of human USP2 in complex with ubiquitin and 6-thioguanine

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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