8BCR
DENV3 Methyltransferase in complexed with AT-9010 and SAH
Summary for 8BCR
| Entry DOI | 10.2210/pdb8bcr/pdb |
| Descriptor | Genome polyprotein, S-ADENOSYLMETHIONINE, [[(2R,3R,4R,5R)-5-(2-azanyl-6-oxidanylidene-1H-purin-9-yl)-4-fluoranyl-4-methyl-3-oxidanyl-oxolan-2-yl]methoxy-oxidanyl-phosphoryl] phosphono hydrogen phosphate, ... (6 entities in total) |
| Functional Keywords | methyltransferase domain of dengue virus 3, viral protein |
| Biological source | Dengue virus type 3 |
| Total number of polymer chains | 2 |
| Total formula weight | 63830.64 |
| Authors | Gauffre, P.,Fattorini, V.,Canard, B.,Ferron, F. (deposition date: 2022-10-17, release date: 2023-03-22, Last modification date: 2024-02-07) |
| Primary citation | Feracci, M.,Eydoux, C.,Fattorini, V.,Lo Bello, L.,Gauffre, P.,Selisko, B.,Sutto-Ortiz, P.,Shannon, A.,Xia, H.,Shi, P.Y.,Noel, M.,Debart, F.,Vasseur, J.J.,Good, S.,Lin, K.,Moussa, A.,Sommadossi, J.P.,Chazot, A.,Alvarez, K.,Guillemot, J.C.,Decroly, E.,Ferron, F.,Canard, B. AT-752 targets multiple sites and activities on the Dengue virus replication enzyme NS5. Antiviral Res., 212:105574-105574, 2023 Cited by PubMed Abstract: AT-752 is a guanosine analogue prodrug active against dengue virus (DENV). In infected cells, it is metabolized into 2'-methyl-2'-fluoro guanosine 5'-triphosphate (AT-9010) which inhibits RNA synthesis in acting as a RNA chain terminator. Here we show that AT-9010 has several modes of action on DENV full-length NS5. AT-9010 does not inhibit the primer pppApG synthesis step significantly. However, AT-9010 targets two NS5-associated enzyme activities, the RNA 2'-O-MTase and the RNA-dependent RNA polymerase (RdRp) at its RNA elongation step. Crystal structure and RNA methyltransferase (MTase) activities of the DENV 2 MTase domain in complex with AT-9010 at 1.97 Å resolution shows the latter bound to the GTP/RNA-cap binding site, accounting for the observed inhibition of 2'-O but not N7-methylation activity. AT-9010 is discriminated ∼10 to 14-fold against GTP at the NS5 active site of all four DENV1-4 NS5 RdRps, arguing for significant inhibition through viral RNA synthesis termination. In Huh-7 cells, DENV1-4 are equally sensitive to AT-281, the free base of AT-752 (EC ≈ 0.50 μM), suggesting broad spectrum antiviral properties of AT-752 against flaviviruses. PubMed: 36905944DOI: 10.1016/j.antiviral.2023.105574 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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