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==Structures of REV1 UBM2 domain complex with ubiquitin and with the first small-molecule that inhibits the REV1 UBM2-ubiquitin interaction==
==Structures of REV1 UBM2 domain complex with ubiquitin and with the first small-molecule that inhibits the REV1 UBM2-ubiquitin interaction==
<StructureSection load='6axd' size='340' side='right' caption='[[6axd]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
<StructureSection load='6axd' size='340' side='right'caption='[[6axd]]' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6axd]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6AXD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6AXD FirstGlance]. <br>
<table><tr><td colspan='2'>[[6axd]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6AXD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6AXD FirstGlance]. <br>
</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=6axd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6axd OCA], [http://pdbe.org/6axd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6axd RCSB], [http://www.ebi.ac.uk/pdbsum/6axd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6axd ProSAT]</span></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</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=6axd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6axd OCA], [https://pdbe.org/6axd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6axd RCSB], [https://www.ebi.ac.uk/pdbsum/6axd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6axd ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/REV1_HUMAN REV1_HUMAN]] Deoxycytidyl transferase involved in DNA repair. Transfers a dCMP residue from dCTP to the 3'-end of a DNA primer in a template-dependent reaction. May assist in the first step in the bypass of abasic lesions by the insertion of a nucleotide opposite the lesion. Required for normal induction of mutations by physical and chemical agents.<ref>PMID:10536157</ref> <ref>PMID:10760286</ref> <ref>PMID:11278384</ref> <ref>PMID:11485998</ref> <ref>PMID:22266823</ref>
[https://www.uniprot.org/uniprot/REV1_HUMAN REV1_HUMAN] Deoxycytidyl transferase involved in DNA repair. Transfers a dCMP residue from dCTP to the 3'-end of a DNA primer in a template-dependent reaction. May assist in the first step in the bypass of abasic lesions by the insertion of a nucleotide opposite the lesion. Required for normal induction of mutations by physical and chemical agents.<ref>PMID:10536157</ref> <ref>PMID:10760286</ref> <ref>PMID:11278384</ref> <ref>PMID:11485998</ref> <ref>PMID:22266823</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
REV1 is a DNA damage tolerance protein and encodes two ubiquitin-binding motifs (UBM1 and UBM2) that are essential for REV1 functions in cell survival under DNA-damaging stress. Here we report the first solution and X-ray crystal structures of REV1 UBM2 and its complex with ubiquitin, respectively. Furthermore, we have identified the first small-molecule compound, MLAF50, that directly binds to REV1 UBM2. In the heteronuclear single quantum coherence NMR experiments, peaks of UBM2 but not of UBM1 are significantly shifted by the addition of ubiquitin, which agrees to the observation that REV1 UBM2 but not UBM1 is required for DNA damage tolerance. REV1 UBM2 interacts with hydrophobic residues of ubiquitin such as L8 and L73. NMR data suggest that MLAF50 binds to the same residues of REV1 UBM2 that interact with ubiquitin, indicating that MLAF50 can compete with the REV1 UBM2-ubiquitin interaction orthosterically. Indeed, MLAF50 inhibited the interaction of REV1 UBM2 with ubiquitin and prevented chromatin localization of REV1 induced by cisplatin in U2OS cells. Our results structurally validate REV1 UBM2 as a target of a small-molecule inhibitor and demonstrate a new avenue to targeting ubiquitination-mediated protein interactions with a chemical tool.


Structures of REV1 UBM2 Domain Complex with Ubiquitin and with a Small-Molecule that Inhibits the REV1 UBM2-Ubiquitin Interaction.,Vanarotti M, Grace CR, Miller DJ, Actis ML, Inoue A, Evison BJ, Vaithiyalingam S, Singh AP, McDonald ET, Fujii N J Mol Biol. 2018 Jun 2. pii: S0022-2836(18)30553-9. doi:, 10.1016/j.jmb.2018.05.042. PMID:29864443<ref>PMID:29864443</ref>
==See Also==
 
*[[DNA polymerase 3D structures|DNA polymerase 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6axd" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Fujii, N]]
[[Category: Homo sapiens]]
[[Category: Vanarotti, M]]
[[Category: Large Structures]]
[[Category: Structural protein]]
[[Category: Fujii N]]
[[Category: Transferase-transferase inhibitor complex]]
[[Category: Vanarotti M]]
[[Category: Ubiquitin-binding motif]]

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