title: Molecular modeling and analysis of hepatitis E virus (HEV) papain-like cysteine protease.
abstract: The biochemical or biophysical characterization of a papain-like cysteine protease in HEV ORF1-encoded polyprotein still remains elusive. Very recently, we have demonstrated the indispensability of ORF1 protease-domain cysteines and histidines in HEV replication, ex vivo (Parvez, 2013). In this report, the polyprotein partial sequences of HEV strains and genetically-related RNA viruses were analyzed, in silico. Employing the consensus-prediction results of RUBV-p(150) protease as structural-template, a 3D model of HEV-protease was deduced. Similar to RUBV-p(150), a 'papain-like β-barrel fold' structurally confirmed the classification of HEV-protease. Further, we recognized a catalytic 'Cys434-His443' dyad homologue of RUBV-p(150) (Cys1152-His1273) and FMDV-L(pro) (Cys51-His148) in line with our previous mutational analysis that showed essentiality of 'His443' but not 'His590' in HEV viability. Moreover, a RUBV 'Zn(2+) binding motif' (Cys1167-Cys1175-Cys1178-Cys1225-Cys1227) equivalent of HEV was identified as 'Cys457-His458-Cys459 and Cys481-Cys483' residues within the 'β-barrel fold'. Notably, unlike RUBV, 'His458' also clustered therein, that was in conformity with the consensus cysteine protease 'Zn(2+)-binding motif'. By homology, we also proposed an overlapping 'Ca(2+)-binding site' 'D-X-[DNS]-[ILVFYW]-[DEN]-G-[GP]-XX-DE' signature, and a 'proline-rich motif' interacting 'tryptophan (W437-W472)' module in the modeled structure. Our analysis of the predicted model therefore, warrants critical roles of the 'catalytic dyad' and 'divalent metal-binding motifs' in HEV protease structural-integrity, ORF1 self-processing, and RNA replication. This however, needs further experimental validations.
authors: Department of Pharmacognosy, King Saud University College of Pharmacy, Riyadh 11451, Saudi Arabia. Electronic address: Khalid_parve@yahoo.com.
authors: Mohammad Khalid
authors: MK
authors: Parvez
authors: Department of Pharmaceutical Chemistry, King Saud University College of Pharmacy, Riyadh 11451, Saudi Arabia.
authors: Azmat Ali
authors: AA
authors: Khan
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D057056:Cysteine Proteases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016752:Hepatitis E virus / Q000737:chemistry / Q000201:enzymology* / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015032:Zinc / Q000737:chemistry / Q000378:metabolism
chemical_list: D014764:Viral Proteins; D057056:Cysteine Proteases; D015032:Zinc
keywords: Ca(2+)-binding motif; Catalytic dyad; HEV-protease model; Hepatitis E virus; ORF1; Papain-like cysteine protease; WW-module; Zn(2+)-binding motif