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| Title | Cryo-EM structures of CCHFV polymerase reveal a stepwise initiation stabilization pathway and a dual-site inhibition mechanism. |
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| Journal, issue, pages | Cell Rep, Vol. 45, Issue 9, Page 117945, Year 2026 |
| Publish date | Sep 3, 2026 |
Authors | Kankan Yang / Haiqiang Wu / Xunbi Liu / Zuxing Liang / Junwei Zou / Yong Wang / Jun Ma / ![]() |
| PubMed Abstract | Crimean-Congo hemorrhagic fever virus (CCHFV) is a high-priority pathogen with high case-fatality rates, yet approved therapeutics remain unavailable. The CCHFV L segment encodes a ∼450-kDa RNA- ...Crimean-Congo hemorrhagic fever virus (CCHFV) is a high-priority pathogen with high case-fatality rates, yet approved therapeutics remain unavailable. The CCHFV L segment encodes a ∼450-kDa RNA-dependent RNA polymerase (L protein) orchestrating viral replication, but its structural mechanisms remain elusive. Here, we present high-resolution cryo-EM structures of the CCHFV L protein in apo, 5' vRNA-bound, 5'/3' promoter-bound, and inhibitor-bound states. The catalytic core exhibits the canonical architecture of the Bunyavirales order, featuring conserved motifs and coordinated promoter recognition via a 5' vRNA "hook" and a secondary 3' vRNA-binding site. Using suramin as a probe, we identified a dual-site mechanism of polymerase inhibition. Suramin competitively occludes the 5' vRNA-binding pocket through electrostatic mimicry of the RNA backbone and concurrently traps a distal linker-fingers interface, restricting the conformational dynamics required for catalysis. Collectively, these findings provide structural insights into CCHFV polymerase regulation and inhibition. |
External links | Cell Rep / PubMed:42696455 |
| Methods | EM (single particle) |
| Resolution | 2.5 - 3.03 Å |
| Structure data | EMDB-68655, PDB-22te: EMDB-68657, PDB-22th: EMDB-68663, PDB-22tr: EMDB-80706, PDB-26jz: EMDB-80707, PDB-26ka: EMDB-80708, PDB-26kb: EMDB-80710, PDB-26kd: |
| Chemicals | ![]() ChemComp-ZN: ![]() ChemComp-MN: ![]() ChemComp-MG: ![]() ChemComp-SVR: |
| Source |
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Keywords | RNA BINDING PROTEIN / Polymerase / RNA BINDING PROTEIN/RNA / RNA BINDING PROTEIN-RNA complex |
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orthonairovirus haemorrhagiae
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