25XM

Cryo-EM structure of the Crimean-Congo hemorrhagic fever virus L protein (5'-cRNA-bound form)

Summary for 25XM

• Entry DOI: 10.2210/pdb25xm/pdb
• EMDB information: 80448
• Descriptor: RNA-directed RNA polymerase L, RNA (5'-R(*UP*CP*UP*CP*AP*AP*AP*GP*AP*UP*AP*UP*CP*A)-3'), ZINC ION (3 entities in total)
• Functional Keywords: negative-strand rna virus, crimean-congo hemorrhagic fever virus, rna-dependent rna polymerase, replication, transcription/rna, replication-rna complex, viral protein/rna, viral protein-rna complex
• Biological source: Orthonairovirus haemorrhagiae; More
• Total number of polymer chains: 2
• Total formula weight: 457748.82

Authors

Jia, H.,Liu, S.,Gong, P. (deposition date: 2026-04-22, release date: 2026-08-05, Last modification date: 2026-09-09)

Primary citation

Jia, H.,Tang, B.,Liu, S.,Wen, X.,Wu, F.,Hu, X.,Zhou, H.,Chong, T.,Lv, L.,Liu, Q.,Rao, G.,Wei, M.,Jing, X.,Cao, S.,Deng, F.,Hu, Z.,Shu, B.,Gong, R.,Wu, J.,Wang, M.,Gong, P.
RNA synthesis and substrate analogue inhibition in the CCHFV polymerase.
Nature, 2026

PubMed Abstract: The about 4,000-residue L proteins from the Nairoviridae are the largest known viral polymerases, lacking global structural information and promising nucleotide analogue inhibitors. Here we report structures of full-length Nairoviridae Crimean-Congo haemorrhagic fever virus (CCHFV) L, including a 3.0 Å resolution polymerase elongation complex that elucidates mechanisms of both early and late elongation stages. Large additions and insertions are found in all three major functional regions that contain the endonuclease RNA-dependent RNA polymerase (RdRP) and cap-binding domain of CCHFV L, extending RNA-binding paths on both sides of the RdRP active site and creating interaction networks critical for viral replication, as suggested by CCHFV minigenome assay data. Nucleotide analogues with ribose-2' modifications identical to the hepatitis C drug sofosbuvir are found to specifically and efficiently inhibit CCHFV RdRP through an immediate chain termination mechanism. Using a sofosbuvir-hepatitis C virus RdRP system as the reference, the potency of these nucleotide analogues is further demonstrated in competition assays in the presence of corresponding nucleoside triphosphates.

PubMed: 42649282
DOI: 10.1038/s41586-026-10913-w

Experimental method

ELECTRON MICROSCOPY (2.67 Å)