7ujn
From Proteopedia
(Difference between revisions)
| Line 1: | Line 1: | ||
==Structure of Human SAMHD1 with Non-Hydrolysable dGTP Analog== | ==Structure of Human SAMHD1 with Non-Hydrolysable dGTP Analog== | ||
| - | <StructureSection load='7ujn' size='340' side='right'caption='[[7ujn]]' scene=''> | + | <StructureSection load='7ujn' size='340' side='right'caption='[[7ujn]], [[Resolution|resolution]] 2.89Å' 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=7UJN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UJN FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7ujn]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7UJN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UJN FirstGlance]. <br> |
| - | </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=7ujn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ujn OCA], [https://pdbe.org/7ujn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ujn RCSB], [https://www.ebi.ac.uk/pdbsum/7ujn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ujn ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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=7ujn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ujn OCA], [https://pdbe.org/7ujn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ujn RCSB], [https://www.ebi.ac.uk/pdbsum/7ujn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ujn ProSAT]</span></td></tr> | ||
</table> | </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 == | ||
| + | SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) is driven into its activated tetramer form by binding of GTP activator and dNTP activators/substrates. In addition, the inactive monomeric and dimeric forms of the enzyme bind to single-stranded (ss) nucleic acids. During DNA replication SAMHD1 can be phosphorylated by CDK1 and CDK2 at its C-terminal threonine 592 (pSAMHD1), localizing the enzyme to stalled replication forks (RFs) to promote their restart. Although phosphorylation has only a small effect on the dNTPase activity and ssDNA binding affinity of SAMHD1, perturbation of the native T592 by phosphorylation decreased the thermal stability of tetrameric SAMHD1 and accelerated tetramer dissociation in the absence and presence of ssDNA ( approximately 15-fold). In addition, we found that ssDNA binds competitively with GTP to the A1 site. A full-length SAMHD1 cryo-EM structure revealed substantial dynamics in the C-terminal domain (which contains T592), which could be modulated by phosphorylation. We propose that T592 phosphorylation increases tetramer dynamics and allows invasion of ssDNA into the A1 site and the previously characterized DNA binding surface at the dimer-dimer interface. These features are consistent with rapid and regiospecific inactivation of pSAMHD1 dNTPase at RFs or other sites of free ssDNA in cells. | ||
| + | |||
| + | Phosphorylation of SAMHD1 Thr592 increases C-terminal domain dynamics, tetramer dissociation and ssDNA binding kinetics.,Orris B, Huynh KW, Ammirati M, Han S, Bolanos B, Carmody J, Petroski MD, Bosbach B, Shields DJ, Stivers JT Nucleic Acids Res. 2022 Jul 22;50(13):7545-7559. doi: 10.1093/nar/gkac573. PMID:35801923<ref>PMID:35801923</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7ujn" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Ammirati M]] | + | [[Category: Ammirati, M]] |
| - | [[Category: Han S]] | + | [[Category: Han, S]] |
| - | [[Category: Huynh | + | [[Category: Huynh, K W]] |
| + | [[Category: Dntp triphosphatase]] | ||
| + | [[Category: Hydrolase]] | ||
Revision as of 05:03, 3 August 2022
Structure of Human SAMHD1 with Non-Hydrolysable dGTP Analog
| |||||||||||
