2in2

NMR Structure of the Apo Human Rhinovirus 3C Protease (serotype 14)

spinqualitylabelsall models 2in2, 20 NMR models Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2in2 is a 1 chain structure with sequence from Hrv-14. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Related: 2b0f, 1cqq, 1l1n Gene: HRV-3ABC (HRV-14) Activity: Picornain 3C, with EC number 3.4.22.28 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [POLG_HRV14] Capsid proteins VP1, VP2, VP3 and VP4 form a closed capsid enclosing the viral positive strand RNA genome. VP4 lies on the inner surface of the protein shell formed by VP1, VP2 and VP3. All the three latter proteins contain a beta-sheet structure called beta-barrel jelly roll. Together they form an icosahedral capsid (T=3) composed of 60 copies of each VP1, VP2, and VP3, with a diameter of approximately 300 Angstroms. VP1 is situated at the 12 fivefold axes, whereas VP2 and VP3 are located at the quasi-sixfold axes (By similarity). The capsid interacts with human ICAM1 to provide virion attachment to target cell. This attachment induces virion internalization predominantly through clathrin- and caveolin-independent endocytosis. VP0 precursor is a component of immature procapsids (By similarity). Protein 2A is a cysteine protease that is responsible for the cleavage between the P1 and P2 regions. It cleaves the host translation initiation factor EIF4G1, in order to shut down the capped cellular mRNA transcription (By similarity). Protein 2B affects membrane integrity and cause an increase in membrane permeability (By similarity). Protein 2C associates with and induces structural rearrangements of intracellular membranes. It displays RNA-binding, nucleotide binding and NTPase activities (By similarity). Protein 3A, via its hydrophobic domain, serves as membrane anchor (By similarity). Protein 3C is a cysteine protease that generates mature viral proteins from the precursor polyprotein. In addition to its proteolytic activity, it binds to viral RNA, and thus influences viral genome replication. RNA and substrate bind co-operatively to the protease (By similarity). RNA-directed RNA polymerase 3D-POL replicates genomic and antigenomic RNA by recognizing replications specific signals (By similarity). Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed The human rhinovirus (HRV) is a positive sense RNA virus responsible for about 30% of "common colds". It relies on a 182 residue cysteine protease (3C) to proteolytically process its single gene product. Inhibition of this enzyme in vitro and in vivo has consistently demonstrated cessation of viral replication. This suggests that 3C protease inhibitors could serve as good drug candidates. However, significant proteolytic substrate diversity exists within the 110+ known rhinovirus serotypes. To investigate this variability we used NMR to solve the structure of the rhinovirus serotype 14 3C protease (subgenus B) covalently bound to a peptide (acetyl-LEALFQ-ethylpropionate) inhibitor. The inhibitor-bound structure was determined to an overall rmsd of 0.82 A (backbone atoms) and 1.49 A (all heavy atoms). Comparison with the X-ray structure of the serotype 2 HRV 3C protease from subgenus A (51% sequence identity) bound to the inhibitor ruprintrivir allowed the identification of conserved intermolecular interactions involved in proximal substrate binding as well as subgenus differences that might account for the variability observed in SAR studies. To better characterize the 3C protease and investigate the structural and dynamic differences between the apo and bound states we also solved the solution structure of the apo form. The apo structure has an overall rmsd of 1.07 +/- 0.17 A over backbone atoms, which is greater by 0.25 A than what is seen for the inhibited enzyme (2B0F.pdb). This increase is localized to the enzyme's C-terminal beta-barrel domain, which is responsible for recognizing and binding proteolytic substrates. Amide hydrogen exchange dynamics revealed dramatic differences between the two enzyme states. Furthermore, a number of residues exhibited exchange-broadened amide NMR signals in the apo state compared to the inhibited state. The majority of these residues are associated with proteolytic substrate interaction. NMR solution structures of the apo and peptide-inhibited human rhinovirus 3C protease (Serotype 14): structural and dynamic comparison.,Bjorndahl TC, Andrew LC, Semenchenko V, Wishart DS Biochemistry. 2007 Nov 13;46(45):12945-58. Epub 2007 Oct 18. PMID:17944485 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Virus protease

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