3tax

From Proteopedia

(Difference between revisions)

Current revision

A Neutral Diphosphate Mimic Crosslinks the Active Site of Human O-GlcNAc Transferase

Structural highlights

3tax is a 4 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 1.88Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CSK21_HUMAN Catalytic subunit of a constitutively active serine/threonine-protein kinase complex that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine. Regulates numerous cellular processes, such as cell cycle progression, apoptosis and transcription, as well as viral infection. May act as a regulatory node which integrates and coordinates numerous signals leading to an appropriate cellular response. During mitosis, functions as a component of the p53/TP53-dependent spindle assembly checkpoint (SAC) that maintains cyclin-B-CDK1 activity and G2 arrest in response to spindle damage. Also required for p53/TP53-mediated apoptosis, phosphorylating 'Ser-392' of p53/TP53 following UV irradiation. Can also negatively regulate apoptosis. Phosphorylates the caspases CASP9 and CASP2 and the apoptotic regulator NOL3. Phosphorylation protects CASP9 from cleavage and activation by CASP8, and inhibits the dimerization of CASP2 and activation of CASP8. Regulates transcription by direct phosphorylation of RNA polymerases I, II, III and IV. Also phosphorylates and regulates numerous transcription factors including NF-kappa-B, STAT1, CREB1, IRF1, IRF2, ATF1, SRF, MAX, JUN, FOS, MYC and MYB. Phosphorylates Hsp90 and its co-chaperones FKBP4 and CDC37, which is essential for chaperone function. Regulates Wnt signaling by phosphorylating CTNNB1 and the transcription factor LEF1. Acts as an ectokinase that phosphorylates several extracellular proteins. During viral infection, phosphorylates various proteins involved in the viral life cycles of EBV, HSV, HBV, HCV, HIV, CMV and HPV.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Glycosyltransferases (Gtfs) catalyze the formation of a diverse array of glycoconjugates. Small-molecule inhibitors to manipulate Gtf activity in cells have long been sought as tools for understanding Gtf function. Success has been limited because of challenges in designing inhibitors that mimic the negatively charged diphosphate substrates. Here we report the mechanism of action of a small molecule that inhibits O-linked N-acetylglucosamine transferase (OGT), an essential human enzyme that modulates cell signaling pathways by catalyzing a unique intracellular post-translational modification, beta-O-GlcNAcylation. The molecule contains a five-heteroatom dicarbamate core that functions as a neutral diphosphate mimic. One dicarbamate carbonyl reacts with an essential active site lysine that anchors the diphosphate of the nucleotide-sugar substrate. A nearby cysteine then reacts with the lysine adduct to form a carbonyl crosslink in the OGT active site. Though this unprecedented double-displacement mechanism reflects the unique architecture of the OGT active site, related dicarbamate scaffolds may inhibit other enzymes that bind nucleotide-containing substrates.

A neutral diphosphate mimic crosslinks the active site of human O-GlcNAc transferase.,Jiang J, Lazarus MB, Pasquina L, Sliz P, Walker S Nat Chem Biol. 2011 Nov 13;8(1):72-7. doi: 10.1038/nchembio.711. PMID:22082911^[5]

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

References

↑ Keller DM, Zeng X, Wang Y, Zhang QH, Kapoor M, Shu H, Goodman R, Lozano G, Zhao Y, Lu H. A DNA damage-induced p53 serine 392 kinase complex contains CK2, hSpt16, and SSRP1. Mol Cell. 2001 Feb;7(2):283-92. PMID:11239457
↑ Sayed M, Pelech S, Wong C, Marotta A, Salh B. Protein kinase CK2 is involved in G2 arrest and apoptosis following spindle damage in epithelial cells. Oncogene. 2001 Oct 25;20(48):6994-7005. PMID:11704824 doi:10.1038/sj.onc.1204894
↑ Shin S, Lee Y, Kim W, Ko H, Choi H, Kim K. Caspase-2 primes cancer cells for TRAIL-mediated apoptosis by processing procaspase-8. EMBO J. 2005 Oct 19;24(20):3532-42. Epub 2005 Sep 29. PMID:16193064 doi:10.1038/sj.emboj.7600827
↑ St-Denis NA, Derksen DR, Litchfield DW. Evidence for regulation of mitotic progression through temporal phosphorylation and dephosphorylation of CK2alpha. Mol Cell Biol. 2009 Apr;29(8):2068-81. doi: 10.1128/MCB.01563-08. Epub 2009 Feb, 2. PMID:19188443 doi:10.1128/MCB.01563-08
↑ Jiang J, Lazarus MB, Pasquina L, Sliz P, Walker S. A neutral diphosphate mimic crosslinks the active site of human O-GlcNAc transferase. Nat Chem Biol. 2011 Nov 13;8(1):72-7. doi: 10.1038/nchembio.711. PMID:22082911 doi:10.1038/nchembio.711

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/3tax"

@@ Line 1: / Line 1: @@
-[[Image:3tax.jpg|left|200px]]
-<!--
+==A Neutral Diphosphate Mimic Crosslinks the Active Site of Human O-GlcNAc Transferase==
-The line below this paragraph, containing "STRUCTURE_3tax", creates the "Structure Box" on the page.
+<StructureSection load='3tax' size='340' side='right'caption='[[3tax]], [[Resolution|resolution]] 1.88&Aring;' scene=''>
-You may change the PDB parameter (which sets the PDB file loaded into the applet)
+== Structural highlights ==
-or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
+<table><tr><td colspan='2'>[[3tax]] is a 4 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=3TAX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3TAX FirstGlance]. <br>
-or leave the SCENE parameter empty for the default display.
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.88&#8491;</td></tr>
--->
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FOR:FORMYL+GROUP'>FOR</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=UDP:URIDINE-5-DIPHOSPHATE'>UDP</scene></td></tr>
-{{STRUCTURE_3tax|  PDB=3tax  |  SCENE=  }}
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3tax FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tax OCA], [https://pdbe.org/3tax PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3tax RCSB], [https://www.ebi.ac.uk/pdbsum/3tax PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3tax ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/CSK21_HUMAN CSK21_HUMAN] Catalytic subunit of a constitutively active serine/threonine-protein kinase complex that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine. Regulates numerous cellular processes, such as cell cycle progression, apoptosis and transcription, as well as viral infection. May act as a regulatory node which integrates and coordinates numerous signals leading to an appropriate cellular response. During mitosis, functions as a component of the p53/TP53-dependent spindle assembly checkpoint (SAC) that maintains cyclin-B-CDK1 activity and G2 arrest in response to spindle damage. Also required for p53/TP53-mediated apoptosis, phosphorylating 'Ser-392' of p53/TP53 following UV irradiation. Can also negatively regulate apoptosis. Phosphorylates the caspases CASP9 and CASP2 and the apoptotic regulator NOL3. Phosphorylation protects CASP9 from cleavage and activation by CASP8, and inhibits the dimerization of CASP2 and activation of CASP8. Regulates transcription by direct phosphorylation of RNA polymerases I, II, III and IV. Also phosphorylates and regulates numerous transcription factors including NF-kappa-B, STAT1, CREB1, IRF1, IRF2, ATF1, SRF, MAX, JUN, FOS, MYC and MYB. Phosphorylates Hsp90 and its co-chaperones FKBP4 and CDC37, which is essential for chaperone function. Regulates Wnt signaling by phosphorylating CTNNB1 and the transcription factor LEF1. Acts as an ectokinase that phosphorylates several extracellular proteins. During viral infection, phosphorylates various proteins involved in the viral life cycles of EBV, HSV, HBV, HCV, HIV, CMV and HPV.<ref>PMID:11239457</ref> <ref>PMID:11704824</ref> <ref>PMID:16193064</ref> <ref>PMID:19188443</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Glycosyltransferases (Gtfs) catalyze the formation of a diverse array of glycoconjugates. Small-molecule inhibitors to manipulate Gtf activity in cells have long been sought as tools for understanding Gtf function. Success has been limited because of challenges in designing inhibitors that mimic the negatively charged diphosphate substrates. Here we report the mechanism of action of a small molecule that inhibits O-linked N-acetylglucosamine transferase (OGT), an essential human enzyme that modulates cell signaling pathways by catalyzing a unique intracellular post-translational modification, beta-O-GlcNAcylation. The molecule contains a five-heteroatom dicarbamate core that functions as a neutral diphosphate mimic. One dicarbamate carbonyl reacts with an essential active site lysine that anchors the diphosphate of the nucleotide-sugar substrate. A nearby cysteine then reacts with the lysine adduct to form a carbonyl crosslink in the OGT active site. Though this unprecedented double-displacement mechanism reflects the unique architecture of the OGT active site, related dicarbamate scaffolds may inhibit other enzymes that bind nucleotide-containing substrates.
-===A Neutral Diphosphate Mimic Crosslinks the Active Site of Human O-GlcNAc Transferase===
+A neutral diphosphate mimic crosslinks the active site of human O-GlcNAc transferase.,Jiang J, Lazarus MB, Pasquina L, Sliz P, Walker S Nat Chem Biol. 2011 Nov 13;8(1):72-7. doi: 10.1038/nchembio.711. PMID:22082911<ref>PMID:22082911</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 3tax" style="background-color:#fffaf0;"></div>
-==About this Structure==
+==See Also==
-[[3tax]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TAX OCA].
+*[[O-GlcNAc transferase 3D structures|O-GlcNAc transferase 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Non-specific serine/threonine protein kinase]]
+[[Category: Large Structures]]
-[[Category: Jiang, J.]]
+[[Category: Jiang J]]
-[[Category: Lazarus, M B.]]
+[[Category: Lazarus MB]]
-[[Category: Pasquina, L.]]
+[[Category: Pasquina L]]
-[[Category: Sliz, P.]]
+[[Category: Sliz P]]
-[[Category: Walker, S.]]
+[[Category: Walker S]]
-[[Category: Covalent inhibitor]]
-[[Category: Gylcosyltransferase inhibitor]]
-[[Category: O-glcnac transferase]]
-[[Category: Thiocarbamate crosslink]]
-[[Category: Transferase]]
-[[Category: Transferase-transferase inhibitor complex]]

3tax

From Proteopedia

Current revision

A Neutral Diphosphate Mimic Crosslinks the Active Site of Human O-GlcNAc Transferase

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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