7a5y
From Proteopedia
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==Crystal structure of tetrameric human H215A-SAMHD1 (residues 109-626) with Rp-dGTP-alphaS (T8T) and Mg== | ==Crystal structure of tetrameric human H215A-SAMHD1 (residues 109-626) with Rp-dGTP-alphaS (T8T) and Mg== | ||
| - | <StructureSection load='7a5y' size='340' side='right'caption='[[7a5y]]' scene=''> | + | <StructureSection load='7a5y' size='340' side='right'caption='[[7a5y]], [[Resolution|resolution]] 2.29Å' 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=7A5Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7A5Y FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7a5y]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7A5Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7A5Y 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=7a5y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7a5y OCA], [https://pdbe.org/7a5y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7a5y RCSB], [https://www.ebi.ac.uk/pdbsum/7a5y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7a5y 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=FE:FE+(III)+ION'>FE</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=T8T:2-DEOXYGUANOSINE-5-O-(1-THIOTRIPHOSPHATE)'>T8T</scene></td></tr> |
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SAMHD1, MOP5 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=7a5y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7a5y OCA], [https://pdbe.org/7a5y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7a5y RCSB], [https://www.ebi.ac.uk/pdbsum/7a5y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7a5y 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 == | ||
| + | SAMHD1 is a fundamental regulator of cellular dNTPs that catalyzes their hydrolysis into 2'-deoxynucleoside and triphosphate, restricting the replication of viruses, including HIV-1, in CD4(+) myeloid lineage and resting T-cells. SAMHD1 mutations are associated with the autoimmune disease Aicardi-Goutieres syndrome (AGS) and certain cancers. More recently, SAMHD1 has been linked to anticancer drug resistance and the suppression of the interferon response to cytosolic nucleic acids after DNA damage. Here, we probe dNTP hydrolysis and inhibition of SAMHD1 using the Rp and Sp diastereomers of dNTPalphaS nucleotides. Our biochemical and enzymological data show that the alpha-phosphorothioate substitution in Sp-dNTPalphaS but not Rp-dNTPalphaS diastereomers prevents Mg(2+) ion coordination at both the allosteric and catalytic sites, rendering SAMHD1 unable to form stable, catalytically active homotetramers or hydrolyze substrate dNTPs at the catalytic site. Furthermore, we find that Sp-dNTPalphaS diastereomers competitively inhibit dNTP hydrolysis, while Rp-dNTPalphaS nucleotides stabilize tetramerization and are hydrolyzed with similar kinetic parameters to cognate dNTPs. For the first time, we present a cocrystal structure of SAMHD1 with a substrate, Rp-dGTPalphaS, in which an Fe-Mg-bridging water species is poised for nucleophilic attack on the P(alpha). We conclude that it is the incompatibility of Mg(2+), a hard Lewis acid, and the alpha-phosphorothioate thiol, a soft Lewis base, that prevents the Sp-dNTPalphaS nucleotides coordinating in a catalytically productive conformation. On the basis of these data, we present a model for SAMHD1 stereospecific hydrolysis of Rp-dNTPalphaS nucleotides and for a mode of competitive inhibition by Sp-dNTPalphaS nucleotides that competes with formation of the enzyme-substrate complex. | ||
| + | |||
| + | Probing the Catalytic Mechanism and Inhibition of SAMHD1 Using the Differential Properties of Rp- and Sp-dNTPalphaS Diastereomers.,Morris ER, Kunzelmann S, Caswell SJ, Purkiss AG, Kelly G, Taylor IA Biochemistry. 2021 May 14. doi: 10.1021/acs.biochem.0c00944. PMID:33988981<ref>PMID:33988981</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7a5y" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Caswell | + | [[Category: Caswell, S J]] |
| - | [[Category: Kunzelmann S]] | + | [[Category: Kunzelmann, S]] |
| - | [[Category: Morris | + | [[Category: Morris, E R]] |
| - | [[Category: Purkiss A]] | + | [[Category: Purkiss, A]] |
| - | [[Category: Taylor | + | [[Category: Taylor, I A]] |
| + | [[Category: Binuclear]] | ||
| + | [[Category: Hd]] | ||
| + | [[Category: Hydrolase]] | ||
| + | [[Category: Metallo-enzyme]] | ||
| + | [[Category: Triphosphohydrolase]] | ||
Revision as of 12:27, 9 June 2021
Crystal structure of tetrameric human H215A-SAMHD1 (residues 109-626) with Rp-dGTP-alphaS (T8T) and Mg
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