9lgp
Crystal structure of the HRV B14 3C protease in complex with AG7404
Structural highlights
FunctionPOLG_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). Publication Abstract from PubMedHuman rhinoviruses (hRVs) are major causative agents of the common cold and contribute to lower respiratory tract infections. Although extensive research efforts continue to explore potential therapeutic interventions, no clinically approved antiviral treatment currently exists for hRV infections. This study provides the structural basis of hRV 3C protease inhibition in several serotypes by AG7404, a modified rupintrivir derivative. AG7404 showed potent antiviral activity against hRV-B14, hRV-A16 and hRV-A21 with EC(50) values of 0.108, 0.191 and 0.187 microM, respectively, and directly inhibited purified hRV-B14 3C protease with an IC(50) of 0.046 microM. The 2.11 A crystal structure of hRV-B14 3C protease in complex with AG7404 revealed covalent binding to the catalytic Cys146 and occupation of the substrate-binding pockets by the ligand. Comparative structural analyses incorporating ligand-free hRV-B14 3C protease structures as well as rupintrivir-bound 3C protease structures from other hRV serotypes revealed significant conformational variability of the betacII-betadII region. Molecular dynamics simulations of the structural models of hRV-A16 and hRV-A21 3C proteases showed that the binding interactions of AG7404, including critical water-mediated networks, are conserved across serotypes despite sequence variations. These findings offer structural insights into the binding mode of AG7404 and establish a foundation for the rational design of broad-spectrum antivirals targeting hRV 3C proteases. Structural insights into the antiviral efficacy of AG7404 against human rhinovirus 3C proteases.,Lee J, Lee HL, Kim H, Gil Y, Lee SH, Jung YS, Shin JS, Jo I IUCrJ. 2026 Jan 1. doi: 10.1107/S2052252525008929. PMID:41212032[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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