| Structural highlights
Function
L_HRSVA Displays RNA-directed RNA polymerase, mRNA guanylyl transferase, mRNA (guanine-N(7)-)-methyltransferase and poly(A) synthetase activities. The viral mRNA guanylyl transferase displays a different biochemical reaction than the cellular enzyme. The template is composed of the viral RNA tightly encapsidated by the nucleoprotein (N). Functions either as transcriptase or as replicase. The transcriptase synthesizes subsequently the subgenomic RNAs, assuring their capping and polyadenylation by a stuttering mechanism. The replicase mode is dependent on intracellular protein N concentration. In this mode, the polymerase replicates the whole viral genome without recognizing the transcriptional signals (By similarity).[1]
Publication Abstract from PubMed
The respiratory syncytial virus polymerase complex, consisting of the polymerase (L) and phosphoprotein (P), catalyzes nucleotide polymerization, cap addition, and cap methylation via the RNA dependent RNA polymerase, capping, and Methyltransferase domains on L. Several nucleoside and non-nucleoside inhibitors have been reported to inhibit this polymerase complex, but the structural details of the exact inhibitor-polymerase interactions have been lacking. Here, we report a non-nucleoside inhibitor JNJ-8003 with sub-nanomolar inhibition potency in both antiviral and polymerase assays. Our 2.9 A resolution cryo-EM structure revealed that JNJ-8003 binds to an induced-fit pocket on the capping domain, with multiple interactions consistent with its tight binding and resistance mutation profile. The minigenome and gel-based de novo RNA synthesis and primer extension assays demonstrated that JNJ-8003 inhibited nucleotide polymerization at the early stages of RNA transcription and replication. Our results support that JNJ-8003 binding modulates a functional interplay between the capping and RdRp domains, and this molecular insight could accelerate the design of broad-spectrum antiviral drugs.
Structural and mechanistic insights into the inhibition of respiratory syncytial virus polymerase by a non-nucleoside inhibitor.,Yu X, Abeywickrema P, Bonneux B, Behera I, Anson B, Jacoby E, Fung A, Adhikary S, Bhaumik A, Carbajo RJ, De Bruyn S, Miller R, Patrick A, Pham Q, Piassek M, Verheyen N, Shareef A, Sutto-Ortiz P, Ysebaert N, Van Vlijmen H, Jonckers THM, Herschke F, McLellan JS, Decroly E, Fearns R, Grosse S, Roymans D, Sharma S, Rigaux P, Jin Z Commun Biol. 2023 Oct 21;6(1):1074. doi: 10.1038/s42003-023-05451-4. PMID:37865687[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Barik S. The structure of the 5' terminal cap of the respiratory syncytial virus mRNA. J Gen Virol. 1993 Mar;74 ( Pt 3):485-90. PMID:8445369
- ↑ Yu X, Abeywickrema P, Bonneux B, Behera I, Anson B, Jacoby E, Fung A, Adhikary S, Bhaumik A, Carbajo RJ, De Bruyn S, Miller R, Patrick A, Pham Q, Piassek M, Verheyen N, Shareef A, Sutto-Ortiz P, Ysebaert N, Van Vlijmen H, Jonckers THM, Herschke F, McLellan JS, Decroly E, Fearns R, Grosse S, Roymans D, Sharma S, Rigaux P, Jin Z. Structural and mechanistic insights into the inhibition of respiratory syncytial virus polymerase by a non-nucleoside inhibitor. Commun Biol. 2023 Oct 21;6(1):1074. PMID:37865687 doi:10.1038/s42003-023-05451-4
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