9I81

SARS-CoV-2 RdRp bound to a stack of three HeE1-2Tyr molecules

Summary for 9I81

• Entry DOI: 10.2210/pdb9i81/pdb
• EMDB information: 52704
• Descriptor: RNA-directed RNA polymerase nsp12, Non-structural protein 8, Non-structural protein 7, ... (4 entities in total)
• Functional Keywords: sars-cov-2 rdrp small molecule inhibitor, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2; More
• Total number of polymer chains: 4
• Total formula weight: 166131.64

Authors

Kabinger, F.,Doze, V.,Schmitzova, J.,Lidschreiber, M.,Dienemann, C.,Cramer, P. (deposition date: 2025-02-04, release date: 2025-03-05, Last modification date: 2025-03-26)

Primary citation

Kabinger, F.,Doze, V.,Schmitzova, J.,Lidschreiber, M.,Dienemann, C.,Cramer, P.
Structural basis of SARS-CoV-2 polymerase inhibition by nonnucleoside inhibitor HeE1-2Tyr.
Proc.Natl.Acad.Sci.USA, 122:e2419854122-e2419854122, 2025

PubMed Abstract: Targeting the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 with small molecules is a promising therapeutic strategy against COVID-19, but potent and safe inhibitors are lacking. HeE1-2Tyr, a nonnucleoside inhibitor of Dengue virus RdRp, was also shown to inhibit SARS-CoV-2 RdRp in vitro and to have antiviral activity in cells, but the underlying mechanism remains unclear. Here, we elucidate the molecular mechanism of HeE1-2Tyr-mediated SARS-CoV-2 RdRp inhibition. Biochemical assays confirm that HeE1-2Tyr inhibits RdRp with an IC of 5 µM and show that it competes with RNA binding to RdRp in vitro. Structural analysis using cryo-EM reveals that a stack of three HeE1-2Tyr molecules binds to the RNA binding site of RdRp. The identification of the conserved HeE1-2Tyr binding site and its intriguing inhibition mechanism of three stacked molecules that outcompete RNA may facilitate further development of pan-corona nonnucleoside inhibitors.

PubMed: 40035759
DOI: 10.1073/pnas.2419854122

Experimental method

ELECTRON MICROSCOPY (2.98 Å)