View source for 5aho


==Crystal structure of human 5' exonuclease Apollo==
<StructureSection load='5aho' size='340' side='right'caption='[[5aho]], [[Resolution|resolution]] 2.16&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5aho]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=3zdk 3zdk]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AHO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5AHO 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]] 2.16&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</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=5aho FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aho OCA], [https://pdbe.org/5aho PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5aho RCSB], [https://www.ebi.ac.uk/pdbsum/5aho PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5aho ProSAT]</span></td></tr>
</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 human SNM1A and SNM1B/Apollo proteins are members of an extended family of eukaryotic nuclease containing a motif related to the prokaryotic metallo-beta-lactamase (MBL) fold. SNM1A is a key exonuclease during replication-dependent and transcription-coupled interstrand crosslink repair, while SNM1B/Apollo is required for maintaining telomeric overhangs. Here, we report the crystal structures of SNM1A and SNM1B at 2.16 A. While both proteins contain a typical MBL-beta-CASP domain, a region of positive charge surrounds the active site of SNM1A, which is absent in SNM1B and explains the greater apparent processivity of SNM1A. The structures of both proteins also reveal a putative, wide DNA-binding groove. Extensive mutagenesis of this groove, coupled with detailed biochemical analysis, identified residues that did not impact on SNM1A catalytic activity, but drastically reduced its processivity. Moreover, we identified a key role for this groove for efficient digestion past DNA interstrand crosslinks, facilitating the key DNA repair reaction catalysed by SNM1A. Together, the architecture and dimensions of this groove, coupled to the surrounding region of high positive charge, explain the remarkable ability of SNM1A to accommodate and efficiently digest highly distorted DNA substrates, such as those containing DNA lesions.

The structures of the SNM1A and SNM1B/Apollo nuclease domains reveal a potential basis for their distinct DNA processing activities.,Allerston CK, Lee SY, Newman JA, Schofield CJ, McHugh PJ, Gileadi O Nucleic Acids Res. 2015 Dec 15;43(22):11047-60. doi: 10.1093/nar/gkv1256. Epub, 2015 Nov 17. PMID:26582912<ref>PMID:26582912</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5aho" style="background-color:#fffaf0;"></div>

==See Also==
*[[Exonuclease 3D structures|Exonuclease 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Allerston CK]]
[[Category: Arrowsmith CH]]
[[Category: Bountra C]]
[[Category: Carpenter E]]
[[Category: Edwards A]]
[[Category: Gileadi O]]
[[Category: Krojer T]]
[[Category: Mahajan P]]
[[Category: Newman JA]]
[[Category: Pike ACW]]
[[Category: Quigley A]]
[[Category: Vollmar M]]
[[Category: Von Delft F]]