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| | ==Crystal structure of the human UBR-box domain from UBR1 in complex with monomethylated arginine peptide.== | | ==Crystal structure of the human UBR-box domain from UBR1 in complex with monomethylated arginine peptide.== |
| - | <StructureSection load='5tdc' size='340' side='right' caption='[[5tdc]], [[Resolution|resolution]] 1.61Å' scene=''> | + | <StructureSection load='5tdc' size='340' side='right'caption='[[5tdc]], [[Resolution|resolution]] 1.61Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5tdc]] is a 4 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=5TDC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TDC FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5tdc]] 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=5TDC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TDC FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.607Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=NMM:(2S)-2-AMINO-5-[(N-METHYLCARBAMIMIDOYL)AMINO]PENTANOIC+ACID'>NMM</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NMM:(2S)-2-AMINO-5-[(N-METHYLCARBAMIMIDOYL)AMINO]PENTANOIC+ACID'>NMM</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5tda|5tda]], [[5tdb|5tdb]], [[5tdd|5tdd]]</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5tdc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tdc OCA], [https://pdbe.org/5tdc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tdc RCSB], [https://www.ebi.ac.uk/pdbsum/5tdc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tdc ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">UBR1 ([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=5tdc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tdc OCA], [http://pdbe.org/5tdc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tdc RCSB], [http://www.ebi.ac.uk/pdbsum/5tdc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tdc ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/UBR1_HUMAN UBR1_HUMAN]] Johanson-Blizzard syndrome. The disease is caused by mutations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/UBR1_HUMAN UBR1_HUMAN] Johanson-Blizzard syndrome. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/UBR1_HUMAN UBR1_HUMAN]] E3 ubiquitin-protein ligase which is a component of the N-end rule pathway. Recognizes and binds to proteins bearing specific N-terminal residues that are destabilizing according to the N-end rule, leading to their ubiquitination and subsequent degradation. May be involved in pancreatic homeostasis. Binds leucine and is a negative regulator of the leucine-mTOR signaling pathway, thereby controlling cell growth.<ref>PMID:15548684</ref> <ref>PMID:16311597</ref> <ref>PMID:20298436</ref> <ref>PMID:20835242</ref> | + | [https://www.uniprot.org/uniprot/UBR1_HUMAN UBR1_HUMAN] E3 ubiquitin-protein ligase which is a component of the N-end rule pathway. Recognizes and binds to proteins bearing specific N-terminal residues that are destabilizing according to the N-end rule, leading to their ubiquitination and subsequent degradation. May be involved in pancreatic homeostasis. Binds leucine and is a negative regulator of the leucine-mTOR signaling pathway, thereby controlling cell growth.<ref>PMID:15548684</ref> <ref>PMID:16311597</ref> <ref>PMID:20298436</ref> <ref>PMID:20835242</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5tdc" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5tdc" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Gehring, K]] | + | [[Category: Large Structures]] |
| - | [[Category: Kozlov, G]] | + | [[Category: Gehring K]] |
| - | [[Category: Matta-Camacho, E]] | + | [[Category: Kozlov G]] |
| - | [[Category: Munoz-Escobar, J]] | + | [[Category: Matta-Camacho E]] |
| - | [[Category: Ligase]]
| + | [[Category: Munoz-Escobar J]] |
| - | [[Category: Monomethylated arginine]]
| + | |
| - | [[Category: N-degron]]
| + | |
| - | [[Category: N-end rule]]
| + | |
| - | [[Category: Ubr-box]]
| + | |
| Structural highlights
Disease
UBR1_HUMAN Johanson-Blizzard syndrome. The disease is caused by mutations affecting the gene represented in this entry.
Function
UBR1_HUMAN E3 ubiquitin-protein ligase which is a component of the N-end rule pathway. Recognizes and binds to proteins bearing specific N-terminal residues that are destabilizing according to the N-end rule, leading to their ubiquitination and subsequent degradation. May be involved in pancreatic homeostasis. Binds leucine and is a negative regulator of the leucine-mTOR signaling pathway, thereby controlling cell growth.[1] [2] [3] [4]
Publication Abstract from PubMed
The N-end rule pathway controls the half-life of proteins based on their N-terminal residue. Positively charged type 1 N-degrons are recognized by a negatively charged pocket on the Zn finger named the UBR box. Here, we show that the UBR box is rigid, but bound water molecules in the pocket provide the structural plasticity required to bind different positively charged amino acids. Ultra-high-resolution crystal structures of arginine, histidine, and methylated arginine reveal that water molecules mediate the binding of N-degron peptides. Using a high-throughput binding assay and isothermal titration calorimetry, we demonstrate that the UBR box is able to bind methylated arginine and lysine peptides with high affinity and measure the preference for hydrophobic residues in the second position in the N-degron peptide. Finally, we show that the V122L mutation present in Johanson-Blizzard syndrome patients changes the specificity for the second position due to occlusion of the secondary pocket.
Bound Waters Mediate Binding of Diverse Substrates to a Ubiquitin Ligase.,Munoz-Escobar J, Matta-Camacho E, Cho C, Kozlov G, Gehring K Structure. 2017 Mar 27. pii: S0969-2126(17)30064-3. doi:, 10.1016/j.str.2017.03.004. PMID:28392261[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kwak KS, Zhou X, Solomon V, Baracos VE, Davis J, Bannon AW, Boyle WJ, Lacey DL, Han HQ. Regulation of protein catabolism by muscle-specific and cytokine-inducible ubiquitin ligase E3alpha-II during cancer cachexia. Cancer Res. 2004 Nov 15;64(22):8193-8. PMID:15548684 doi:http://dx.doi.org/64/22/8193
- ↑ Zenker M, Mayerle J, Lerch MM, Tagariello A, Zerres K, Durie PR, Beier M, Hulskamp G, Guzman C, Rehder H, Beemer FA, Hamel B, Vanlieferinghen P, Gershoni-Baruch R, Vieira MW, Dumic M, Auslender R, Gil-da-Silva-Lopes VL, Steinlicht S, Rauh M, Shalev SA, Thiel C, Ekici AB, Winterpacht A, Kwon YT, Varshavsky A, Reis A. Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson-Blizzard syndrome). Nat Genet. 2005 Dec;37(12):1345-50. Epub 2005 Nov 20. PMID:16311597 doi:http://dx.doi.org/10.1038/ng1681
- ↑ Kume K, Iizumi Y, Shimada M, Ito Y, Kishi T, Yamaguchi Y, Handa H. Role of N-end rule ubiquitin ligases UBR1 and UBR2 in regulating the leucine-mTOR signaling pathway. Genes Cells. 2010 Apr 1;15(4):339-49. doi: 10.1111/j.1365-2443.2010.01385.x. Epub, 2010 Mar 16. PMID:20298436 doi:http://dx.doi.org/10.1111/j.1365-2443.2010.01385.x
- ↑ Matta-Camacho E, Kozlov G, Li FF, Gehring K. Structural basis of substrate recognition and specificity in the N-end rule pathway. Nat Struct Mol Biol. 2010 Oct;17(10):1182-7. Epub 2010 Sep 12. PMID:20835242 doi:10.1038/nsmb.1894
- ↑ Munoz-Escobar J, Matta-Camacho E, Cho C, Kozlov G, Gehring K. Bound Waters Mediate Binding of Diverse Substrates to a Ubiquitin Ligase. Structure. 2017 Mar 27. pii: S0969-2126(17)30064-3. doi:, 10.1016/j.str.2017.03.004. PMID:28392261 doi:http://dx.doi.org/10.1016/j.str.2017.03.004
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