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| <StructureSection load='6yhr' size='340' side='right'caption='[[6yhr]], [[Resolution|resolution]] 2.20Å' scene=''> | | <StructureSection load='6yhr' size='340' side='right'caption='[[6yhr]], [[Resolution|resolution]] 2.20Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[6yhr]] is a 1 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=6YHR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YHR FirstGlance]. <br> | | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YHR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YHR FirstGlance]. <br> |
| </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2Å</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]] 2.2Å</td></tr> |
| <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=6yhr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yhr OCA], [https://pdbe.org/6yhr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yhr RCSB], [https://www.ebi.ac.uk/pdbsum/6yhr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yhr ProSAT]</span></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=6yhr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yhr OCA], [https://pdbe.org/6yhr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yhr RCSB], [https://www.ebi.ac.uk/pdbsum/6yhr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yhr ProSAT]</span></td></tr> |
| </table> | | </table> |
| == Disease ==
| |
| [https://www.uniprot.org/uniprot/WRN_HUMAN WRN_HUMAN] Defects in WRN are a cause of Werner syndrome (WRN) [MIM:[https://omim.org/entry/277700 277700]. WRN is a rare autosomal recessive progeroid syndrome characterized by the premature onset of multiple age-related disorders, including atherosclerosis, cancer, non-insulin-dependent diabetes mellitus, ocular cataracts and osteoporosis. The major cause of death, at a median age of 47, is myocardial infarction. Currently all known WS mutations produces prematurely terminated proteins.<ref>PMID:16673358</ref> Defects in WRN may be a cause of colorectal cancer (CRC) [MIM:[https://omim.org/entry/114500 114500].
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| == Function ==
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| [https://www.uniprot.org/uniprot/WRN_HUMAN WRN_HUMAN] Multifunctional enzyme that has both magnesium and ATP-dependent DNA-helicase activity and 3'->5' exonuclease activity towards double-stranded DNA with a 5'-overhang. Has no nuclease activity towards single-stranded DNA or blunt-ended double-stranded DNA. Binds preferentially to DNA substrates containing alternate secondary structures, such as replication forks and Holliday junctions. May play an important role in the dissociation of joint DNA molecules that can arise as products of homologous recombination, at stalled replication forks or during DNA repair. Alleviates stalling of DNA polymerases at the site of DNA lesions. Important for genomic integrity. Plays a role in the formation of DNA replication focal centers; stably associates with foci elements generating binding sites for RP-A (By similarity).<ref>PMID:11863428</ref> <ref>PMID:17563354</ref> <ref>PMID:18596042</ref> <ref>PMID:19652551</ref> <ref>PMID:19283071</ref>
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| <div style="background-color:#fffaf0;">
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| == Publication Abstract from PubMed ==
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| Loss of WRN, a DNA repair helicase, was identified as a strong vulnerability of microsatellite instable (MSI) cancers, making WRN a promising drug target. We show that ATP binding and hydrolysis are required for genome integrity and viability of MSI cancer cells. We report a 2.2-A crystal structure of the WRN helicase core (517-1,093), comprising the two helicase subdomains and winged helix domain but not the HRDC domain or nuclease domains. The structure highlights unusual features. First, an atypical mode of nucleotide binding that results in unusual relative positioning of the two helicase subdomains. Second, an additional beta-hairpin in the second helicase subdomain and an unusual helical hairpin in the Zn(2+) binding domain. Modelling of the WRN helicase in complex with DNA suggests roles for these features in the binding of alternative DNA structures. NMR analysis shows a weak interaction between the HRDC domain and the helicase core, indicating a possible biological role for this association. Together, this study will facilitate the structure-based development of inhibitors against WRN helicase.
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| Structure of the helicase core of Werner helicase, a key target in microsatellite instability cancers.,Newman JA, Gavard AE, Lieb S, Ravichandran MC, Hauer K, Werni P, Geist L, Bottcher J, Engen JR, Rumpel K, Samwer M, Petronczki M, Gileadi O Life Sci Alliance. 2020 Nov 16;4(1). pii: 4/1/e202000795. doi:, 10.26508/lsa.202000795. Print 2021 Jan. PMID:33199508<ref>PMID:33199508</ref>
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| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| <div class="pdbe-citations 6yhr" style="background-color:#fffaf0;"></div>
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| ==See Also== | | ==See Also== |
| *[[Helicase 3D structures|Helicase 3D structures]] | | *[[Helicase 3D structures|Helicase 3D structures]] |
| == References ==
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| <references/>
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| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Homo sapiens]]
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| [[Category: Large Structures]] | | [[Category: Large Structures]] |
| [[Category: Arrowsmith CH]] | | [[Category: Arrowsmith CH]] |