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Study On The Structure And Function Of Poliovirus 2C Protein

Posted on:2019-11-27Degree:MasterType:Thesis
Country:ChinaCandidate:J TianFull Text:PDF
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Poliovirus(PV)is the pathogen of poliomyelitis.PV belongs to Enterovirus C species in the Enterovirus genus,Picornaviridae family.It has an icosahedral non-enveloped capsid enveloping a single-stranded +RNA genome of?7,500 nucleotides which can encode a polyprotein.The polyprotein needs to be cleaved to 11 final products which contain four structure proteins(capsid protein):VP1,VP2 VP3 and VP4 and seven non-structure proteins:2A,2B,2C,3A,3B,3C and 3D by protease 2A and 3C.PV 2C is the most studied 2C helicase in Picornaviridae family.It is involved in RNA replication,encapsidation and uncoating and many inhibitors were found targeting PV 2C.High-resolution structure of PV 2C remained unavailable for decades despite numerous investigations have been carried out to characterize its functions.We report here the crystal structure of a soluble fragment of PV 2C to 2.5 5A,containing an ATPase domain,a zinc finger and a C-terminal helical domain but missing the N-terminal domain.The ATPase domain shares the common structural features with EV71 2C and other Superfamily 3 helicases.The C-terminal cysteine-rich motif folds into a CCCC type zinc finger with four cysteine ligands and several auxiliary residues assisting zinc binding.Comparing with the known zinc finger fold groups,we found that the zinc finger of 2C helicases belongs to a new fold group,and we denoted it "Enterovirus 2C-like" group.The C-terminus of PV 2C is an amphipathic helix that occupies a hydrophobic pocket located on an adjacent PV 2C.The C-terminus mediated PV 2C-2C interaction promotes self-oligomerization,most possible hexamerization,which is fundamental to ATPase activity of 2C.The zinc finger is the most structurally diverse site in 2C helicases.Available structural and virological results suggest that the zinc finger of 2C might confer the specificity of interaction with other proteins.We built a hexameric ring model of PV 2C based on SV40 Large T Antigen.The hexameric ring models of PV 2C and EV71 2C show that the ATPase active site formed between 2C-2C has nearly identical geometry and the catalytic residues(Walker A&B,Motif C and R-finger)identified by structural and biochemical characterizations are invariant.We visualized the previously identified functional motifs and drug-resistant sites,thus provided a structure framework for antiviral drug development.
Keywords/Search Tags:poliovirus, 2C helicase, zinc-finger, crystal structure, antivirals
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