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8pyw
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of the human Nucleoside-diphosphate kinase B domain bound to compound diphosphate form of AT-9052-Sp.== | |
| + | <StructureSection load='8pyw' size='340' side='right'caption='[[8pyw]], [[Resolution|resolution]] 1.55Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8pyw]] is a 6 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=8PYW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8PYW 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]] 1.553Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IF9:[[(2R,3R,4R,5R)-5-(2-azanyl-6-oxidanylidene-1H-purin-9-yl)-4-fluoranyl-4-methyl-3-oxidanyl-oxolan-2-yl]methoxy-sulfanyl-phosphoryl]+dihydrogen+phosphate'>IF9</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=8pyw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8pyw OCA], [https://pdbe.org/8pyw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8pyw RCSB], [https://www.ebi.ac.uk/pdbsum/8pyw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8pyw ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/NDKB_HUMAN NDKB_HUMAN] Major role in the synthesis of nucleoside triphosphates other than ATP. Negatively regulates Rho activity by interacting with AKAP13/LBC. Acts as a transcriptional activator of the MYC gene; binds DNA non-specifically (PubMed:8392752). Exhibits histidine protein kinase activity.<ref>PMID:15249197</ref> <ref>PMID:20946858</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Nucleotide analogues (NA) are currently employed for treatment of several viral diseases, including COVID-19. NA prodrugs are intracellularly activated to the 5'-triphosphate form. They are incorporated into the viral RNA by the viral polymerase (SARS-CoV-2 nsp12), terminating or corrupting RNA synthesis. For Coronaviruses, natural resistance to NAs is provided by a viral 3'-to-5' exonuclease heterodimer nsp14/nsp10, which can remove terminal analogues. Here, we show that the replacement of the alpha-phosphate of Bemnifosbuvir 5'-triphosphate form (AT-9010) by an alpha-thiophosphate renders it resistant to excision. The resulting alpha-thiotriphosphate, AT-9052, exists as two epimers (RP/SP). Through co-crystallization and activity assays, we show that the Sp isomer is preferentially used as a substrate by nucleotide diphosphate kinase (NDPK), and by SARS-CoV-2 nsp12, where its incorporation causes immediate chain-termination. The same -Sp isomer, once incorporated by nsp12, is also totally resistant to the excision by nsp10/nsp14 complex. However, unlike AT-9010, AT-9052-RP/SP no longer inhibits the N-terminal nucleotidylation domain of nsp12. We conclude that AT-9052-Sp exhibits a unique mechanism of action against SARS-CoV-2. Moreover, the thio modification provides a general approach to rescue existing NAs whose activity is hampered by coronavirus proofreading capacity. | ||
| - | + | An exonuclease-resistant chain-terminating nucleotide analogue targeting the SARS-CoV-2 replicase complex.,Shannon A, Chazot A, Feracci M, Falcou C, Fattorini V, Selisko B, Good S, Moussa A, Sommadossi JP, Ferron F, Alvarez K, Canard B Nucleic Acids Res. 2023 Dec 14:gkad1194. doi: 10.1093/nar/gkad1194. PMID:38096103<ref>PMID:38096103</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: Chazot | + | <div class="pdbe-citations 8pyw" style="background-color:#fffaf0;"></div> |
| - | [[Category: Feracci | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Chazot A]] | ||
| + | [[Category: Feracci M]] | ||
Revision as of 23:14, 27 December 2023
Crystal structure of the human Nucleoside-diphosphate kinase B domain bound to compound diphosphate form of AT-9052-Sp.
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