4mdk

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{{STRUCTURE_4mdk| PDB=4mdk | SCENE= }}
 
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===Cdc34-ubiquitin-CC0651 complex===
 
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==Function==
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==Cdc34-ubiquitin-CC0651 complex==
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[[http://www.uniprot.org/uniprot/UB2R1_HUMAN UB2R1_HUMAN]] Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-48'-linked polyubiquitination. Cooperates with the E2 UBCH5C and the SCF(FBXW11) E3 ligase complex for the polyubiquitination of NFKBIA leading to its subsequent proteasomal degradation. Performs ubiquitin chain elongation building ubiquitin chains from the UBE2D3-primed NFKBIA-linked ubiquitin. UBE2D3 acts as an initiator E2, priming the phosphorylated NFKBIA target at positions 'Lys-21' and/or 'Lys-22' with a monoubiquitin. Cooperates with the SCF(SKP2) E3 ligase complex to regulate cell proliferation through ubiquitination and degradation of MYBL2 and KIP1. Involved in ubiquitin conjugation and degradation of CREM isoform ICERIIgamma and ATF15 resulting in abrogation of ICERIIgamma- and ATF5-mediated repression of cAMP-induced transcription during both meiotic and mitotic cell cycles. Involved in the regulation of the cell cycle G2/M phase through its targeting of the WEE1 kinase for ubiquitination and degradation. Also involved in the degradation of beta-catenin. Is target of human herpes virus 1 protein ICP0, leading to ICP0-dependent dynamic interaction with proteasomes.<ref>PMID:10329681</ref> <ref>PMID:10373550</ref> <ref>PMID:10871850</ref> <ref>PMID:11675391</ref> <ref>PMID:12037680</ref> <ref>PMID:15652359</ref> <ref>PMID:17461777</ref> <ref>PMID:17698585</ref> <ref>PMID:19945379</ref> <ref>PMID:19126550</ref> <ref>PMID:20061386</ref> <ref>PMID:20347421</ref> [[http://www.uniprot.org/uniprot/UBC_HUMAN UBC_HUMAN]] 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.<ref>PMID:16543144</ref> <ref>PMID:19754430</ref>
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<StructureSection load='4mdk' size='340' side='right'caption='[[4mdk]], [[Resolution|resolution]] 2.61&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4mdk]] is a 8 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=4MDK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MDK FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6095&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=U94:4,5-DIDEOXY-5-(3,5-DICHLOROBIPHENYL-4-YL)-4-[(METHOXYACETYL)AMINO]-L-ARABINONIC+ACID'>U94</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4mdk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mdk OCA], [https://pdbe.org/4mdk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mdk RCSB], [https://www.ebi.ac.uk/pdbsum/4mdk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mdk ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/UB2R1_HUMAN UB2R1_HUMAN] Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-48'-linked polyubiquitination. Cooperates with the E2 UBCH5C and the SCF(FBXW11) E3 ligase complex for the polyubiquitination of NFKBIA leading to its subsequent proteasomal degradation. Performs ubiquitin chain elongation building ubiquitin chains from the UBE2D3-primed NFKBIA-linked ubiquitin. UBE2D3 acts as an initiator E2, priming the phosphorylated NFKBIA target at positions 'Lys-21' and/or 'Lys-22' with a monoubiquitin. Cooperates with the SCF(SKP2) E3 ligase complex to regulate cell proliferation through ubiquitination and degradation of MYBL2 and KIP1. Involved in ubiquitin conjugation and degradation of CREM isoform ICERIIgamma and ATF15 resulting in abrogation of ICERIIgamma- and ATF5-mediated repression of cAMP-induced transcription during both meiotic and mitotic cell cycles. Involved in the regulation of the cell cycle G2/M phase through its targeting of the WEE1 kinase for ubiquitination and degradation. Also involved in the degradation of beta-catenin. Is target of human herpes virus 1 protein ICP0, leading to ICP0-dependent dynamic interaction with proteasomes.<ref>PMID:10329681</ref> <ref>PMID:10373550</ref> <ref>PMID:10871850</ref> <ref>PMID:11675391</ref> <ref>PMID:12037680</ref> <ref>PMID:15652359</ref> <ref>PMID:17461777</ref> <ref>PMID:17698585</ref> <ref>PMID:19945379</ref> <ref>PMID:19126550</ref> <ref>PMID:20061386</ref> <ref>PMID:20347421</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Weak protein interactions between ubiquitin and the ubiquitin-proteasome system (UPS) enzymes that mediate its covalent attachment to substrates serve to position ubiquitin for optimal catalytic transfer. We show that a small-molecule inhibitor of the E2 ubiquitin-conjugating enzyme Cdc34A, called CC0651, acts by trapping a weak interaction between ubiquitin and the E2 donor ubiquitin-binding site. A structure of the ternary CC0651-Cdc34A-ubiquitin complex reveals that the inhibitor engages a composite binding pocket formed from Cdc34A and ubiquitin. CC0651 also suppresses the spontaneous hydrolysis rate of the Cdc34A-ubiquitin thioester without decreasing the interaction between Cdc34A and the RING domain subunit of the E3 enzyme. Stabilization of the numerous other weak interactions between ubiquitin and UPS enzymes by small molecules may be a feasible strategy to selectively inhibit different UPS activities.
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==About this Structure==
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E2 enzyme inhibition by stabilization of a low-affinity interface with ubiquitin.,Huang H, Ceccarelli DF, Orlicky S, St-Cyr DJ, Ziemba A, Garg P, Plamondon S, Auer M, Sidhu S, Marinier A, Kleiger G, Tyers M, Sicheri F Nat Chem Biol. 2013 Dec 15. doi: 10.1038/nchembio.1412. PMID:24316736<ref>PMID:24316736</ref>
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[[4mdk]] is a 8 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MDK OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<references group="xtra"/><references/>
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</div>
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[[Category: Ubiquitin--protein ligase]]
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<div class="pdbe-citations 4mdk" style="background-color:#fffaf0;"></div>
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[[Category: Ceccarelli, D F.]]
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[[Category: Orlicky, S.]]
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==See Also==
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[[Category: Sicheri, F.]]
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*[[3D structures of ubiquitin conjugating enzyme|3D structures of ubiquitin conjugating enzyme]]
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[[Category: Tyers, M.]]
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== References ==
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[[Category: E2 ligase inhibitor]]
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<references/>
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[[Category: Ligase-ligase inhibitor complex]]
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__TOC__
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[[Category: Ubiquitin conjugating enzyme domain]]
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Ceccarelli DF]]
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[[Category: Orlicky S]]
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[[Category: Sicheri F]]
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[[Category: Tyers M]]

Current revision

Cdc34-ubiquitin-CC0651 complex

PDB ID 4mdk

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