View source for 4bzc


==Crystal structure of the tetrameric dGTP-bound wild type SAMHD1 catalytic core==
<StructureSection load='4bzc' size='340' side='right'caption='[[4bzc]], [[Resolution|resolution]] 2.88&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4bzc]] is a 4 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=4BZC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BZC 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]] 2.88&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=T8T:2-DEOXYGUANOSINE-5-O-(1-THIOTRIPHOSPHATE)'>T8T</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=4bzc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bzc OCA], [https://pdbe.org/4bzc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bzc RCSB], [https://www.ebi.ac.uk/pdbsum/4bzc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bzc ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/SAMH1_HUMAN SAMH1_HUMAN] Defects in SAMHD1 are the cause of Aicardi-Goutieres syndrome type 5 (AGS5) [MIM:[https://omim.org/entry/612952 612952]. A form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood.<ref>PMID:19525956</ref> <ref>PMID:20842748</ref>   Defects in SAMHD1 are the cause of chilblain lupus type 2 (CHBL2) [MIM:[https://omim.org/entry/614415 614415]. A rare cutaneous form of lupus erythematosus. Affected individuals present with painful bluish-red papular or nodular lesions of the skin in acral locations precipitated by cold and wet exposure at temperatures less than 10 degrees centigrade.<ref>PMID:21204240</ref> 
== Function ==
[https://www.uniprot.org/uniprot/SAMH1_HUMAN SAMH1_HUMAN] Putative nuclease involved in innate immune response by acting as a negative regulator of the cell-intrinsic antiviral response. May play a role in mediating proinflammatory responses to TNF-alpha signaling.<ref>PMID:18546154</ref> <ref>PMID:19525956</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
SAMHD1, a dNTP triphosphohydrolase (dNTPase), has a key role in human innate immunity. It inhibits infection of blood cells by retroviruses, including HIV, and prevents the development of the autoinflammatory Aicardi-Goutieres syndrome (AGS). The inactive apo-SAMHD1 interconverts between monomers and dimers, and in the presence of dGTP the protein assembles into catalytically active tetramers. Here, we present the crystal structure of the human tetrameric SAMHD1-dGTP complex. The structure reveals an elegant allosteric mechanism of activation through dGTP-induced tetramerization of two inactive dimers. Binding of dGTP to four allosteric sites promotes tetramerization and induces a conformational change in the substrate-binding pocket to yield the catalytically active enzyme. Structure-based biochemical and cell-based biological assays confirmed the proposed mechanism. The SAMHD1 tetramer structure provides the basis for a mechanistic understanding of its function in HIV restriction and the pathogenesis of AGS.

Mechanism of allosteric activation of SAMHD1 by dGTP.,Ji X, Wu Y, Yan J, Mehrens J, Yang H, Delucia M, Hao C, Gronenborn AM, Skowronski J, Ahn J, Xiong Y Nat Struct Mol Biol. 2013 Oct 20. doi: 10.1038/nsmb.2692. PMID:24141705<ref>PMID:24141705</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4bzc" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Ahn J]]
[[Category: DeLucia M]]
[[Category: Gronenborn AM]]
[[Category: Hao C]]
[[Category: Ji X]]
[[Category: Mehrens J]]
[[Category: Skowronski J]]
[[Category: Wu Y]]
[[Category: Xiong Y]]
[[Category: Yan J]]
[[Category: Yang H]]