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==Crystal structure of human 5' exonuclease Appollo APO form== | ==Crystal structure of human 5' exonuclease Appollo APO form== | ||
<StructureSection load='7b9b' size='340' side='right'caption='[[7b9b]]' scene=''> | <StructureSection load='7b9b' size='340' side='right'caption='[[7b9b]], [[Resolution|resolution]] 2.80Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7B9B OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[7b9b]] 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=7B9B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7B9B FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.8Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</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=7b9b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7b9b OCA], [https://pdbe.org/7b9b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7b9b RCSB], [https://www.ebi.ac.uk/pdbsum/7b9b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7b9b ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | |||
[https://www.uniprot.org/uniprot/DCR1B_HUMAN DCR1B_HUMAN] Defects in DCLRE1B may be a cause of Hoyeraal-Hreidarsson syndrome (HHS) [MIM:[https://omim.org/entry/300240 300240]. HHS is a multisystem disorder affecting males and is characterized by aplastic anemia, immunodeficiency, microcephaly, cerebellar hypoplasia, and growth retardation. Note=An aberrant splice variant designated Apollo-Delta has been found in a patient with Hoyeraal-Hreidarsson syndrome. Apollo-Delta hampers the proper replication of telomeres, leading to major telomeric dysfunction and cellular senescence, but maintains its DNA interstrand cross-link repair function in the whole genome.<ref>PMID:20479256</ref> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/DCR1B_HUMAN DCR1B_HUMAN] 5'-3' exonuclease that plays a central role in telomere maintenance and protection during S-phase. Participates in the protection of telomeres against non-homologous end-joining (NHEJ)-mediated repair, thereby ensuring that telomeres do not fuse. Plays a key role in telomeric loop (T loop) formation by being recruited by TERF2 at the leading end telomeres and by processing leading-end telomeres immediately after their replication via its exonuclease activity: generates 3' single-stranded overhang at the leading end telomeres avoiding blunt leading-end telomeres that are vulnerable to end-joining reactions and expose the telomere end in a manner that activates the DNA repair pathways. Together with TERF2, required to protect telomeres from replicative damage during replication by controlling the amount of DNA topoisomerase (TOP1, TOP2A and TOP2B) needed for telomere replication during fork passage and prevent aberrant telomere topology. Also involved in response to DNA damage: plays a role in response to DNA interstrand cross-links (ICLs) by facilitating double-strand break formation. In case of spindle stress, involved in prophase checkpoint.<ref>PMID:15572677</ref> <ref>PMID:15467758</ref> <ref>PMID:16730176</ref> <ref>PMID:16730175</ref> <ref>PMID:18468965</ref> <ref>PMID:18469862</ref> <ref>PMID:19197158</ref> <ref>PMID:19411856</ref> <ref>PMID:20655466</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The SNM1 nucleases which help maintain genome integrity are members of the metallo-beta-lactamase (MBL) structural superfamily. Their conserved MBL-beta-CASP-fold SNM1 core provides a molecular scaffold forming an active site which coordinates the metal ions required for catalysis. The features that determine SNM1 endo- versus exonuclease activity, and which control substrate selectivity and binding are poorly understood. We describe a structure of SNM1B/Apollo with two nucleotides bound to its active site, resembling the product state of its exonuclease reaction. The structure enables definition of key SNM1B residues that form contacts with DNA and identifies a 5' phosphate binding pocket, which we demonstrate is important in catalysis and which has a key role in determining endo- versus exonucleolytic activity across the SNM1 family. We probed the capacity of SNM1B to digest past sites of common endogenous DNA lesions and find that base modifications planar to the nucleobase can be accommodated due to the open architecture of the active site, but lesions axial to the plane of the nucleobase are not well tolerated due to constriction around the altered base. We propose that SNM1B/Apollo might employ its activity to help remove common oxidative lesions from telomeres. | |||
A phosphate binding pocket is a key determinant of exo- versus endo-nucleolytic activity in the SNM1 nuclease family.,Baddock HT, Newman JA, Yosaatmadja Y, Bielinski M, Schofield CJ, Gileadi O, McHugh PJ Nucleic Acids Res. 2021 Sep 20;49(16):9294-9309. doi: 10.1093/nar/gkab692. PMID:34387694<ref>PMID:34387694</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7b9b" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Exonuclease 3D structures|Exonuclease 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Arrowshmith CH]] | [[Category: Arrowshmith CH]] | ||