View source for 6tt5


==Crystal structure of DCLRE1C/Artemis==
<StructureSection load='6tt5' size='340' side='right'caption='[[6tt5]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6tt5]] 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=6TT5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TT5 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]] 1.5&#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=NI:NICKEL+(II)+ION'>NI</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=6tt5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tt5 OCA], [https://pdbe.org/6tt5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tt5 RCSB], [https://www.ebi.ac.uk/pdbsum/6tt5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tt5 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/DCR1C_HUMAN DCR1C_HUMAN] Severe combined immunodeficiency, alymphocytotic type;Omenn syndrome. Defects in DCLRE1C are a cause of severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-negative/NK-cell-positive with sensitivity to ionizing radiation (RSSCID) [MIM:[https://omim.org/entry/602450 602450]. SCID refers to a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients with SCID present in infancy with recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development. Individuals affected by RS-SCID show defects in the DNA repair machinery necessary for coding joint formation and the completion of V(D)J recombination. A subset of cells from such patients show increased radiosensitivity.<ref>PMID:11336668</ref> <ref>PMID:12406895</ref> <ref>PMID:12921762</ref> <ref>PMID:12592555</ref> <ref>PMID:12569164</ref>   Defects in DCLRE1C are the cause of severe combined immunodeficiency Athabaskan type (SCIDA) [MIM:[https://omim.org/entry/602450 602450]. SCIDA is a variety of RS-SCID caused by a founder mutation in Athabascan-speaking native Americans, being inherited as an autosomal recessive trait with an estimated gene frequency of 2.1% in the Navajo population. Affected individuals exhibit clinical symptoms and defects in DNA repair comparable to those seen in RS-SCID.<ref>PMID:12055248</ref>   Defects in DCLRE1C are a cause of Omenn syndrome (OS) [MIM:[https://omim.org/entry/603554 603554]. OS is characterized by severe combined immunodeficiency associated with erythrodermia, hepatosplenomegaly, lymphadenopathy and alopecia. Affected individuals have elevated T-lymphocyte counts with a restricted T-cell receptor (TCR) repertoire. They also generally lack B-lymphocytes, but have normal natural killer (NK) cell function (T+ B- NK+).
== Function ==
[https://www.uniprot.org/uniprot/DCR1C_HUMAN DCR1C_HUMAN] Required for V(D)J recombination, the process by which exons encoding the antigen-binding domains of immunoglobulins and T-cell receptor proteins are assembled from individual V, (D), and J gene segments. V(D)J recombination is initiated by the lymphoid specific RAG endonuclease complex, which generates site specific DNA double strand breaks (DSBs). These DSBs present two types of DNA end structures: hairpin sealed coding ends and phosphorylated blunt signal ends. These ends are independently repaired by the non homologous end joining (NHEJ) pathway to form coding and signal joints respectively. This protein exhibits single-strand specific 5'-3' exonuclease activity in isolation and acquires endonucleolytic activity on 5' and 3' hairpins and overhangs when in a complex with PRKDC. The latter activity is required specifically for the resolution of closed hairpins prior to the formation of the coding joint. May also be required for the repair of complex DSBs induced by ionizing radiation, which require substantial end-processing prior to religation by NHEJ.<ref>PMID:11336668</ref> <ref>PMID:12055248</ref> <ref>PMID:11955432</ref> <ref>PMID:15071507</ref> <ref>PMID:15468306</ref> <ref>PMID:14744996</ref> <ref>PMID:15574326</ref> <ref>PMID:15574327</ref> <ref>PMID:15456891</ref> <ref>PMID:15811628</ref> <ref>PMID:15936993</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Artemis (SNM1C/DCLRE1C) is an endonuclease that plays a key role in development of B- and T-lymphocytes and in dsDNA break repair by non-homologous end-joining (NHEJ). Artemis is phosphorylated by DNA-PKcs and acts to open DNA hairpin intermediates generated during V(D)J and class-switch recombination. Artemis deficiency leads to congenital radiosensitive severe acquired immune deficiency (RS-SCID). Artemis belongs to a superfamily of nucleases containing metallo-beta-lactamase (MBL) and beta-CASP (CPSF-Artemis-SNM1-Pso2) domains. We present crystal structures of the catalytic domain of wildtype and variant forms of Artemis, including one causing RS-SCID Omenn syndrome. The catalytic domain of the Artemis has similar endonuclease activity to the phosphorylated full-length protein. Our structures help explain the predominantly endonucleolytic activity of Artemis, which contrasts with the predominantly exonuclease activity of the closely related SNM1A and SNM1B MBL fold nucleases. The structures reveal a second metal binding site in its beta-CASP domain unique to Artemis, which is amenable to inhibition by compounds including ebselen. By combining our structural data with that from a recently reported Artemis structure, we were able model the interaction of Artemis with DNA substrates. The structures, including one of Artemis with the cephalosporin ceftriaxone, will help enable the rational development of selective SNM1 nuclease inhibitors.

Structural and mechanistic insights into the Artemis endonuclease and strategies for its inhibition.,Yosaatmadja Y, Baddock HT, Newman JA, Bielinski M, Gavard AE, Mukhopadhyay SMM, Dannerfjord AA, Schofield CJ, McHugh PJ, Gileadi O Nucleic Acids Res. 2021 Aug 13. pii: 6350767. doi: 10.1093/nar/gkab693. PMID:34387696<ref>PMID:34387696</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6tt5" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Arrowsmith CH]]
[[Category: Bountra C]]
[[Category: Burgess-Brown NA]]
[[Category: Dannerfjord AA]]
[[Category: Edwards A]]
[[Category: Gileadi O]]
[[Category: Goubin S]]
[[Category: Mukhopadhyay SMM]]
[[Category: Newman JA]]
[[Category: Yosaatmadja Y]]
[[Category: Von Delft F]]