3vdd | pdb_00003vdd
Structure of HRV2 capsid complexed with antiviral compound BTA798
Structural highlights
Function[POLG_HRV2] 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. The capsid interacts with human VLDLR to provide virion attachment to target cell. This attachment induces virion internalization predominantly through clathrin-mediated endocytosis. VP4 and VP1 subsequently undergo conformational changes leading to the formation of a pore in the endosomal membrane, thereby delivering the viral genome into the cytoplasm.[1] [2] VP0 precursor is a component of immature procapsids (By similarity).[3] [4] 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.[5] [6] Protein 2B affects membrane integrity and cause an increase in membrane permeability (By similarity).[7] [8] Protein 2C associates with and induces structural rearrangements of intracellular membranes. It displays RNA-binding, nucleotide binding and NTPase activities (By similarity).[9] [10] Protein 3A, via its hydrophobic domain, serves as membrane anchor (By similarity).[11] [12] 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).[13] [14] RNA-directed RNA polymerase 3D-POL replicates genomic and antigenomic RNA by recognizing replications specific signals (By similarity).[15] [16] Publication Abstract from PubMedRespiratory infections caused by human rhinovirus are responsible for severe exacerbations of underlying clinical conditions such as asthma in addition to their economic cost in terms of lost working days due to illness. While several antiviral compounds for treating rhinoviral infections have been discovered, none have succeeded, to date, in reaching approval for clinical use. We have developed a potent, orally available rhinovirus inhibitor 6 that has progressed through early clinical trials. The compound shows favorable pharmacokinetic and activity profiles and has a confirmed mechanism of action through crystallographic studies of a rhinovirus-compound complex. The compound has now progressed to phase IIb clinical studies of its effect on natural rhinovirus infection in humans. An Orally Available 3-Ethoxybenzisoxazole Capsid Binder with Clinical Activity against Human Rhinovirus.,Feil SC, Hamilton S, Krippner GY, Lin B, Luttick A, McConnell DB, Nearn R, Parker MW, Ryan J, Stanislawski PC, Tucker SP, Watson KG, Morton CJ ACS Med Chem Lett. 2012 Feb 13;3(4):303-7. doi: 10.1021/ml2002955. eCollection, 2012 Apr 12. PMID:24900468[17] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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