8PYW
Crystal structure of the human Nucleoside-diphosphate kinase B domain bound to compound diphosphate form of AT-9052-Sp.
Summary for 8PYW
| Entry DOI | 10.2210/pdb8pyw/pdb |
| Descriptor | Nucleoside diphosphate kinase B, GLYCEROL, [[(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, ... (4 entities in total) |
| Functional Keywords | transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 6 |
| Total formula weight | 106627.46 |
| Authors | Feracci, M.,Chazot, A. (deposition date: 2023-07-26, release date: 2023-12-27, Last modification date: 2024-02-21) |
| Primary citation | Shannon, A.,Chazot, A.,Feracci, M.,Falcou, C.,Fattorini, V.,Selisko, B.,Good, S.,Moussa, A.,Sommadossi, J.P.,Ferron, F.,Alvarez, K.,Canard, B. An exonuclease-resistant chain-terminating nucleotide analogue targeting the SARS-CoV-2 replicase complex. Nucleic Acids Res., 52:1325-1340, 2024 Cited by PubMed Abstract: 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 α-phosphate of Bemnifosbuvir 5'-triphosphate form (AT-9010) by an α-thiophosphate renders it resistant to excision. The resulting α-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. PubMed: 38096103DOI: 10.1093/nar/gkad1194 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.553 Å) |
Structure validation
Download full validation report
