5l6i: Difference between revisions

Latest revision as of 16:08, 4 October 2023

Uba1 in complex with Ub-MLN4924 covalent adduct

Structural highlights

5l6i is a 5 chain structure with sequence from Saccharomyces cerevisiae and Saccharomyces cerevisiae S288C. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.76Å
Ligands:	B39, CL, CSO, GOL, SO4
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

UBA1_YEAST Activates ubiquitin by first adenylating its C-terminal glycine residue with ATP, and thereafter linking this residue to the side chain of a cysteine residue in E1, yielding an ubiquitin-E1 thioester and free AMP.

Publication Abstract from PubMed

Targeting the activating enzymes (E1) of ubiquitin (Ub) and ubiquitin-like modifiers (Ubls) has emerged as a promising anti-cancer strategy, possibly overcoming the ineffectiveness of proteasome inhibitors against solid tumors. Here, we report crystal structures of the yeast ubiquitin E1 (Uba1) with three adenosyl sulfamate inhibitors exhibiting different E1 specificities, which are all covalently linked to ubiquitin. The structures illustrate how the chemically diverse inhibitors are accommodated within the adenylation active site. When compared with the previously reported structures of various E1 enzymes, our structures provide the basis of the preferences of these inhibitors for different Ub/Ubl-activating enzymes. In vitro inhibition assays and molecular dynamics simulations validated the specificities of the inhibitors as deduced from the structures. Taken together, the structures establish a framework for the development of additional compounds targeting E1 enzymes, which will display higher potency and selectivity.

Dissecting the Specificity of Adenosyl Sulfamate Inhibitors Targeting the Ubiquitin-Activating Enzyme.,Misra M, Kuhn M, Lobel M, An H, Statsyuk AV, Sotriffer C, Schindelin H Structure. 2017 Jul 5;25(7):1120-1129.e3. doi: 10.1016/j.str.2017.05.001. Epub, 2017 Jun 1. PMID:28578874^[1]

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

References

↑ Misra M, Kuhn M, Lobel M, An H, Statsyuk AV, Sotriffer C, Schindelin H. Dissecting the Specificity of Adenosyl Sulfamate Inhibitors Targeting the Ubiquitin-Activating Enzyme. Structure. 2017 Jul 5;25(7):1120-1129.e3. doi: 10.1016/j.str.2017.05.001. Epub, 2017 Jun 1. PMID:28578874 doi:https://dx.doi.org/10.1016/j.str.2017.05.001

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OCA

[1] Misra M, Kuhn M, Lobel M, An H, Statsyuk AV, Sotriffer C, Schindelin H. Dissecting the Specificity of Adenosyl Sulfamate Inhibitors Targeting the Ubiquitin-Activating Enzyme. Structure. 2017 Jul 5;25(7):1120-1129.e3. doi: 10.1016/j.str.2017.05.001. Epub, 2017 Jun 1. PMID:28578874 doi:https://dx.doi.org/10.1016/j.str.2017.05.001

[1]

@@ Line 3: / Line 3: @@
 <StructureSection load='5l6i' size='340' side='right'caption='[[5l6i]], [[Resolution|resolution]] 2.76&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5l6i]] is a 5 chain structure with sequence from [http://en.wikipedia.org/wiki/Atcc_18824 Atcc 18824] and [http://en.wikipedia.org/wiki/Baker's_yeast Baker's yeast]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5L6I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5L6I FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5l6i]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae] and [https://en.wikipedia.org/wiki/Saccharomyces_cerevisiae_S288C Saccharomyces cerevisiae S288C]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5L6I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5L6I FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=B39:[(1S,2S,4R)-4-{4-[(1S)-2,3-DIHYDRO-1H-INDEN-1-YLAMINO]-7H-PYRROLO[2,3-D]PYRIMIDIN-7-YL}-2-HYDROXYCYCLOPENTYL]METHYL+SULFAMATE'>B39</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.76&#8491;</td></tr>
-<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CSO:S-HYDROXYCYSTEINE'>CSO</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=B39:[(1S,2S,4R)-4-{4-[(1S)-2,3-DIHYDRO-1H-INDEN-1-YLAMINO]-7H-PYRROLO[2,3-D]PYRIMIDIN-7-YL}-2-HYDROXYCYCLOPENTYL]METHYL+SULFAMATE'>B39</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=CSO:S-HYDROXYCYSTEINE'>CSO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">UBA1, YKL210W ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=559292 Baker's yeast]), RPS31, RPS37, UBI3, YLR167W, L9470.14 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=4932 ATCC 18824])</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=5l6i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l6i OCA], [https://pdbe.org/5l6i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5l6i RCSB], [https://www.ebi.ac.uk/pdbsum/5l6i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5l6i ProSAT]</span></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/E1_ubiquitin-activating_enzyme E1 ubiquitin-activating enzyme], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.2.1.45 6.2.1.45] </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=5l6i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l6i OCA], [http://pdbe.org/5l6i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5l6i RCSB], [http://www.ebi.ac.uk/pdbsum/5l6i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5l6i ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/UBA1_YEAST UBA1_YEAST]] Activates ubiquitin by first adenylating its C-terminal glycine residue with ATP, and thereafter linking this residue to the side chain of a cysteine residue in E1, yielding an ubiquitin-E1 thioester and free AMP. [[http://www.uniprot.org/uniprot/RS27A_YEAST RS27A_YEAST]] 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, and DNA-damage responses. 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).  40S ribosomal protein S31 is a component of the 40S subunit of the ribosome (By similarity).
+[https://www.uniprot.org/uniprot/UBA1_YEAST UBA1_YEAST] Activates ubiquitin by first adenylating its C-terminal glycine residue with ATP, and thereafter linking this residue to the side chain of a cysteine residue in E1, yielding an ubiquitin-E1 thioester and free AMP.
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 21: @@
 ==See Also==
-*[[Ubiquitin activating enzyme|Ubiquitin activating enzyme]]
+*[[3D structures of Ubiquitin activating enzyme|3D structures of Ubiquitin activating enzyme]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Atcc 18824]]
-[[Category: Baker's yeast]]
-[[Category: E1 ubiquitin-activating enzyme]]
 [[Category: Large Structures]]
-[[Category: Misra, M]]
+[[Category: Saccharomyces cerevisiae]]
-[[Category: Schindelin, H]]
+[[Category: Saccharomyces cerevisiae S288C]]
-[[Category: Adenosyl sulfamate]]
+[[Category: Misra M]]
-[[Category: E1 enzyme]]
+[[Category: Schindelin H]]
-[[Category: Ligase]]
-[[Category: Uba1 inhibitor]]
-[[Category: Ubiquitin activation]]

5l6i: Difference between revisions

Latest revision as of 16:08, 4 October 2023

Uba1 in complex with Ub-MLN4924 covalent adduct

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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