Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Consecutive catalytic steps of viral RNA polymerase and exonuclease suggest a way to overcome intrinsic nucleotide analogue resistance.
Journal, issue, pages	Proc Natl Acad Sci U S A, Vol. 123, Issue 24, Page e2605725123, Year 2026
Publish date	Jun 16, 2026
Authors	Ashleigh Shannon / Véronique Fattorini / Candice Sartre / Aurélie Chazot / Adel Moussa / Jean-Pierre Sommadossi / Yingxiao Zhu / Manfu Wang / Hui Shi / François Ferron / Karine Alvarez / Bruno Canard /
PubMed Abstract	Nucleotide analogues (NAs) have been successfully used for the treatment of various RNA virus infections by selectively targeting the viral RNA-dependent RNA polymerase (RdRp) for incorporation into ...Nucleotide analogues (NAs) have been successfully used for the treatment of various RNA virus infections by selectively targeting the viral RNA-dependent RNA polymerase (RdRp) for incorporation into the viral genome. However two major families of human-infecting RNA viruses, (CoV) and encode exonuclease domains that may recognize and remove incorporated NAs, thus providing natural resistance against some of these drugs. Both polymerization and excision reactions are mechanistically centered on the nucleotide α-phosphate, enabling the potential for sequential inhibition of both RNA synthesis and repair. Here, we provide structural evidence of inversion of configuration at the phosphorus center during polymerization, demonstrating that the SARS-CoV-2 RdRp proceeds through an S2 mechanism. A 2.39 Å resolution cryo-EM structure of a ternary replication complex bound to RNA and an α-thio-modified NTP shows that incorporation of the preferred isomer at the 3' end of the RNA yields a phosphorothioate linkage in the configuration. This -phosphorothioate RNA product shows reduced cleavage by both the SARS-CoV-2 and three arenavirus RNA exonucleases, revealing a stereochemical preference opposite to that of structurally related DNA exonucleases. This observation contradicts the prevailing assumption that sulfur substitution at the metal-coordinating oxygen universally blocks catalysis. Instead, RNA exonuclease stereoselectivity appears to be shaped not only by metal-sulfur interactions but also by the geometry of nucleophile activation. These findings provide mechanistic insights into phosphoryl transfer in viral polymerases and exonucleases and highlight opportunities to counteract intrinsic nuclease-mediated resistance against antiviral nucleotide analogues.
External links	Proc Natl Acad Sci U S A / PubMed:42263136 / PubMed Central
Methods	EM (single particle)
Resolution	2.39 Å
Structure data	69467 24ew EMDB-69467, PDB-24ew: SARS-CoV-2 polymerase with incorporated and pre-incorporated AT-9052-Sp Method: EM (single particle) / Resolution: 2.39 Å
Chemicals	ChemComp-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 ChemComp-ZN: Unknown entry ChemComp-MG: Unknown entry PDB-1me1: Chimeric hairpin with 2',5'-linked RNA loop and RNA stem ChemComp-POP: PYROPHOSPHATE 2-
Source	severe acute respiratory syndrome coronavirus 2 synthetic construct (others)
Keywords	RNA BINDING PROTEIN / RNA polymerase / RNA Exonuclease / coronavirus / arenavirus / stereospecificity