9VXY

Cryo-EM Structure of Nipah Virus Polymerase in complex with GL22

This is a non-PDB format compatible entry.

Summary for 9VXY

• Entry DOI: 10.2210/pdb9vxy/pdb
• EMDB information: 65445
• Descriptor: RNA-directed RNA polymerase L, Phosphoprotein, ZINC ION, ... (4 entities in total)
• Functional Keywords: polymerase, inhibitor, nipah virus, complex, replication
• Biological source: Henipavirus nipahense; More
• Total number of polymer chains: 5
• Total formula weight: 571944.98

Authors

Xue, L.,Gui, J.,Chang, T.,Pan, H.,Xiong, X. (deposition date: 2025-07-20, release date: 2026-04-29, Last modification date: 2026-05-13)

Primary citation

Xue, L.,Gui, J.,Gao, S.,Gao, X.,Chang, T.,Pan, H.,Tang, J.,Zhang, M.,Li, Z.,Zou, B.,Zhao, H.,Wang, L.,Li, M.,Rong, L.,Plemper, R.K.,Chen, X.,He, J.,Pei, R.,Zhan, P.,Xiong, X.
Differential inhibition of Morbillivirus and Henipavirus polymerases by ERDRP-0519 and structure-guided inhibitor optimization.
Cell, 2026

PubMed Abstract: ERDRP-0519 is a non-nucleoside polymerase inhibitor developed against measles virus (MeV) of the Morbillivirus genus. Here, we show that ERDRP-0519 also cross-inhibits Nipah virus (NiV) of the Henipavirus genus with reduced potency. ERDRP-0519 binds to a shared pocket within the RNA-dependent RNA polymerase (RdRp) palm domains of MeV, peste des petits ruminants virus (PPRV), and NiV polymerases. ERDRP-0519 forms more extensive interactions with Morbillivirus polymerases, whereas binding to NiV polymerase requires substantial RdRp motif rearrangements, likely incurring an energetic cost and resulting in reduced affinity. ERDRP-0519 binding impedes RNA synthesis by sterically blocking RNA and nucleotide binding. Guided by these insights, we designed GL22 and G671, ERDRP-0519 derivatives with extended moieties that engage additional cross-domain RdRp contacts in the NiV polymerase. These derivatives exert more extensive steric hindrance to RNA and nucleotide binding, enhancing biochemical inhibition potency. These findings elucidate the molecular mechanism of ERDRP-0519 action and guide structure-based inhibitor design.

PubMed: 42061399
DOI: 10.1016/j.cell.2026.04.011

Experimental method

ELECTRON MICROSCOPY (2.87 Å)