View source for 8qxl


==Cryo-EM structure of tetrameric human SAMHD1 State II - Hemi-relaxed==
<StructureSection load='8qxl' size='340' side='right'caption='[[8qxl]], [[Resolution|resolution]] 2.82&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8qxl]] 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=8QXL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8QXL FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.82&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3PO:TRIPHOSPHATE'>3PO</scene>, <scene name='pdbligand=DCP:2-DEOXYCYTIDINE-5-TRIPHOSPHATE'>DCP</scene>, <scene name='pdbligand=DCZ:2-DEOXYCYTIDINE'>DCZ</scene>, <scene name='pdbligand=DTP:2-DEOXYADENOSINE+5-TRIPHOSPHATE'>DTP</scene>, <scene name='pdbligand=FE:FE+(III)+ION'>FE</scene>, <scene name='pdbligand=GTP:GUANOSINE-5-TRIPHOSPHATE'>GTP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=8qxl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8qxl OCA], [https://pdbe.org/8qxl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8qxl RCSB], [https://www.ebi.ac.uk/pdbsum/8qxl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8qxl 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 regulates cellular nucleotide homeostasis, controlling dNTP levels by catalysing their hydrolysis into 2'-deoxynucleosides and triphosphate. In differentiated CD4+ macrophage and resting T-cells SAMHD1 activity results in the inhibition of HIV-1 infection through a dNTP blockade. In cancer, SAMHD1 desensitizes cells to nucleoside-analogue chemotherapies. Here we employ time-resolved cryogenic-EM imaging and single-particle analysis to visualise assembly, allostery and catalysis by this multi-subunit enzyme. Our observations reveal how dynamic conformational changes in the SAMHD1 quaternary structure drive the catalytic cycle. We capture five states at high-resolution in a live catalytic reaction, revealing how allosteric activators support assembly of a stable SAMHD1 tetrameric core and how catalysis is driven by the opening and closing of active sites through pairwise coupling of active sites and order-disorder transitions in regulatory domains. This direct visualisation of enzyme catalysis dynamics within an allostery-stabilised platform sets a precedent for mechanistic studies into the regulation of multi-subunit enzymes.

Platform-directed allostery and quaternary structure dynamics of SAMHD1 catalysis.,Acton OJ, Sheppard D, Kunzelmann S, Caswell SJ, Nans A, Burgess AJO, Kelly G, Morris ER, Rosenthal PB, Taylor IA Nat Commun. 2024 May 6;15(1):3775. doi: 10.1038/s41467-024-48237-w. PMID:38710701<ref>PMID:38710701</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8qxl" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Acton OJ]]
[[Category: Rosenthal PB]]
[[Category: Sheppard D]]
[[Category: Taylor IA]]