9VS4

Structure of Ebinur lake virus polymerase complexed with suramin

Summary for 9VS4

• Entry DOI: 10.2210/pdb9vs4/pdb
• EMDB information: 65296
• Descriptor: RNA-directed RNA polymerase L, 8,8'-[CARBONYLBIS[IMINO-3,1-PHENYLENECARBONYLIMINO(4-METHYL-3,1-PHENYLENE)CARBONYLIMINO]]BIS-1,3,5-NAPHTHALENETRISULFON IC ACID (2 entities in total)
• Functional Keywords: viral protein, polymerase, suramin
• Biological source: Ebinur lake virus
• Total number of polymer chains: 1
• Total formula weight: 201633.00

Authors

Tang, J.,Deng, Z. (deposition date: 2025-07-08, release date: 2026-05-13, Last modification date: 2026-05-27)

Primary citation

Tang, J.,Kuang, W.,Chen, W.,Wu, H.,Wang, Y.,Li, J.,Yuan, Z.,Xia, H.,Zhao, H.,Deng, Z.
Structural basis for RNA synthesis and inhibition of the orthobunyavirus polymerase.
Nat Commun, 2026

PubMed Abstract: Orthobunyaviruses are segmented negative-sense RNA viruses that encompass several life-threatening human and animal pathogens. However, no licensed antivirals are currently available. The viral RNA-dependent RNA polymerase (RdRp) is a multi-domain enzyme critical for genome replication and transcription, representing a promising target for antiviral drug development. Here, we establish robust in vitro enzymatic activity assays for the Ebinur Lake virus (EBIV) polymerase and identify suramin, a century-old drug, as an inhibitor of EBIV polymerase. We further determine cryo-EM structures of the EBIV polymerase in apo, elongation, and suramin-bound states. These structures reveal conformational rearrangements of the polymerase during RNA synthesis, including conformational transitions of the prime-and-realign (PR) loop and a unique β-hairpin that bridges the zinc-binding domain (ZBD) to the RdRp core. The structural observations are correlated with in vitro enzymatic activity and cell-based minireplicon assays. The suramin-bound structure reveals two distinct inhibitory binding sites. One site sterically clashes with the vRNA promoter. The other site directly blocks RNA template strand binding, thereby inhibiting polymerase activity. These findings advance our understanding of orthobunyavirus RNA synthesis mechanisms and offer a structural framework for the rational design and optimization of antiviral drugs.

PubMed: 42140913
DOI: 10.1038/s41467-026-72944-1

Experimental method

ELECTRON MICROSCOPY (3 Å)