8XPO
Cryo-EM structure of Lassa virus RdRP elongation complex with the NTP form of compound HNC-1664 bound in the active site
This is a non-PDB format compatible entry.
Summary for 8XPO
| Entry DOI | 10.2210/pdb8xpo/pdb |
| EMDB information | 38557 |
| Descriptor | RNA-directed RNA polymerase L, RNA (14-MER), RNA (32-MER), ... (5 entities in total) |
| Functional Keywords | lassa virus, rna-dependent rna polymerase, elongation complex, nucleoside analog, replication |
| Biological source | Lassa virus Josiah More |
| Total number of polymer chains | 4 |
| Total formula weight | 273533.26 |
| Authors | |
| Primary citation | Jia, X.,Jing, X.,Li, M.,Gao, M.,Zhong, Y.,Li, E.,Liu, Y.,Li, R.,Yao, G.,Liu, Q.,Zhou, M.,Hou, Y.,An, L.,Hong, Y.,Li, S.,Zhang, J.,Wang, W.,Zhang, K.,Gong, P.,Chiu, S. An adenosine analog shows high antiviral potency against coronavirus and arenavirus mainly through an unusual base pairing mode. Nat Commun, 15:10750-10750, 2024 Cited by PubMed Abstract: By targeting the essential viral RNA-dependent RNA polymerase (RdRP), nucleoside analogs (NAs) have exhibited great potential in antiviral therapy for RNA virus-related diseases. However, most ribose-modified NAs do not present broad-spectrum features, likely due to differences in ribose-RdRP interactions across virus families. Here, we show that HNC-1664, an adenosine analog with modifications both in ribose and base, has broad-spectrum antiviral activity against positive-strand coronaviruses and negative-strand arenaviruses. Importantly, treatment with HNC-1664 demonstrate anti-SARS-CoV-2 efficacy in infected K18-human ACE2 mice, with reduced viral titer and mortality, as well as improved lung injury. Enzymology data demonstrate that HNC-1664 inhibits RNA synthesis mainly at the pre-catalysis stage. The cryo-EM structures of HNC-1664-bound RdRP-RNA complexes from both SARS-CoV-2 and LASV reveal an unusual base pairing mode of HNC-1664 in part due to its base modification, thus revealing its great potency in binding but not catalysis. Under certain circumstances, 1664-TP can be slowly incorporated by RdRP through regular Watson-Crick base pairing, as evidenced by enzymology data and an HNC-1664-incorporated crystal structure of the RdRP-RNA complex. Overall, HNC-1664 achieves broad-spectrum characteristics by favoring an alternative base pairing strategy to non-catalytically block RNA synthesis, providing a novel concept for the rational development of NA drugs. PubMed: 39737930DOI: 10.1038/s41467-024-54918-3 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.02 Å) |
Structure validation
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