9wa5
Crystal structure of an inactive form of NS2B-NS3 Protease
Structural highlights
FunctionPOLG_ZIKV Protein C: Encapsulates the genomic RNA.[UniProtKB:P17763] prM: Acts as a chaperone for envelope protein E during intracellular virion assembly by masking and inactivating envelope protein E fusion peptide. prM is matured in the last step of virion assembly, presumably to avoid catastrophic activation of the viral fusion peptide induced by the acidic pH of the trans-Golgi network. After cleavage by host furin, the pr peptide is released in the extracellular medium and small envelope protein M and envelope protein E homodimers are dissociated.[UniProtKB:P17763] Envelope protein E: Binding to host cell surface receptor is followed by virus internalization through clathrin-mediated endocytosis. Envelope protein E is subsequently involved in membrane fusion between virion and host late endosomes. Synthesized as a homodimer with prM which acts as a chaperone for envelope protein E. After cleavage of prM, envelope protein E dissociate from small envelope protein M and homodimerizes.[UniProtKB:P17763] Non-structural protein 1: Involved in virus replication and regulation of the innate immune response.[UniProtKB:P17763] Non-structural protein 2A: May be involved viral RNA replication and capsid assembly.[UniProtKB:P09732] Non-structural protein 4A: Induces host endoplasmic reticulum membrane rearrangements leading to the formation of virus-induced membranous vesicles hosting the dsRNA and polymerase, functioning as a replication complex. NS4A might also regulate the ATPase activity of the helicase region of Serine protease NS3 chain.[UniProtKB:P17763] Peptide 2k: Functions as a signal peptide for NS4B and is required for the interferon antagonism activity of the latter.[UniProtKB:P17763] Non-structural protein 4B: Inhibits interferon (IFN)-induced host STAT1 phosphorylation and nuclear translocation, thereby preventing the establishment of cellular antiviral state by blocking the IFN-alpha/beta pathway.[UniProtKB:P17763] Publication Abstract from PubMedThe Zika virus protease, composed of the cofactor region from NS2B and the N-terminal region of NS3, plays a critical role in viral polyprotein maturation and represents an attractive therapeutic target. However, developing small-molecule inhibitors for its highly hydrophilic active site remains challenging, highlighting the importance of pursuing allosteric inhibition strategies. In this study, we engineered an NS2B-NS3 protease containing an 18-residue NS2B sequence linked to the N-terminal region of NS3 via a glycine-rich linker. We determined its crystal structure and obtained the solution NMR spectrum with backbone resonance assigned. This new construct was used in fragment screening and two new fragments were identified. This design excludes the C-terminal part of NS2B cofactor region, whose conformation is influenced by substrate or inhibitor binding, making the construct particularly valuable for screening and characterizing allosteric inhibitors. An inactive Zika NS2B-NS3pro protease construct for investigating allosteric inhibitors.,Ngo KH, Lattmann S, Anindita PD, Liew CW, Harris RS, Luo D, Kang C J Struct Biol. 2026 Mar 14;218(2):108314. doi: 10.1016/j.jsb.2026.108314. PMID:41833763[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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