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6tal

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3C-like protease from Southampton virus complexed with FMOPL000227a.

Structural highlights

6tal is a 2 chain structure with sequence from Southampton virus (serotype 3). Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.51Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

POLG_SOUV3 Protein p48 may play a role in viral replication by interacting with host VAPA, a vesicle-associated membrane protein that plays a role in SNARE-mediated vesicle fusion. This interaction may target replication complex to intracellular membranes (By similarity). NTPase presumably plays a role in replication. Despite having similarities with helicases, does not seem to display any helicase activity (By similarity). Protein P22 may play a role in targeting replication complex to intracellular membranes. Viral genome-linked protein is covalently linked to the 5'-end of the positive-strand, negative-strand genomic RNAs and subgenomic RNA. Acts as a genome-linked replication primer. May recruit ribosome to viral RNA thereby promoting viral proteins translation (By similarity). 3C-like protease processes the polyprotein: 3CLpro-RdRp is first released by autocleavage, then all other proteins are cleaved. May cleave polyadenylate-binding protein thereby inhibiting cellular translation.[PROSITE-ProRule:PRU00870] RNA-directed RNA polymerase replicates genomic and antigenomic RNA by recognizing replications specific signals. Transcribes also a subgenomic mRNA by initiating RNA synthesis internally on antigenomic RNA. This sgRNA codes for structural proteins. Catalyzes the covalent attachment VPg with viral RNAs (By similarity).[PROSITE-ProRule:PRU00539]

Publication Abstract from PubMed

Outbreaks of human epidemic nonbacterial gastroenteritis are mainly caused by noroviruses. Viral replication requires a 3C-like cysteine protease (3CL(pro)) which processes the 200 kDa viral polyprotein into six functional proteins. The 3CL(pro) has attracted much interest due to its potential as a target for antiviral drugs. A system for growing high-quality crystals of native Southampton norovirus 3CL(pro) (SV3CP) has been established, allowing the ligand-free crystal structure to be determined to 1.3 A in a tetrameric state. This also allowed crystal-based fragment screening to be performed with various compound libraries, ultimately to guide drug discovery for SV3CP. A total of 19 fragments were found to bind to the protease out of the 844 which were screened. Two of the hits were located at the active site of SV3CP and showed good inhibitory activity in kinetic assays. Another 5 were found at the enzyme's putative RNA-binding site and a further 11 were located in the symmetric central cavity of the tetramer.

In crystallo-screening for discovery of human norovirus 3C-like protease inhibitors.,Guo J, Douangamath A, Song W, Coker AR, Chan AWE, Wood SP, Cooper JB, Resnick E, London N, Delft FV J Struct Biol X. 2020 Jul 16;4:100031. doi: 10.1016/j.yjsbx.2020.100031., eCollection 2020. PMID:32743543^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Guo J, Douangamath A, Song W, Coker AR, Chan AWE, Wood SP, Cooper JB, Resnick E, London N, Delft FV. In crystallo-screening for discovery of human norovirus 3C-like protease inhibitors. J Struct Biol X. 2020 Jul 16;4:100031. PMID:32743543 doi:10.1016/j.yjsbx.2020.100031