6jpw

From Proteopedia

Crystal structure of Zika NS2B-NS3 protease with compound 1C

Structural highlights

6jpw is a 11 chain structure with sequence from Zika virus and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.951Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

POLG_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 PubMed

Peptides featuring an N-terminal cysteine residue and the unnatural amino acid 3-(2-cyano-4-pyridyl)alanine (Cpa) cyclize spontaneously in aqueous solution at neutral pH. Cpa is readily available and easily introduced into peptides using standard solid-phase peptide synthesis. The reaction is orthogonal to all proteinogenic amino acids, including cysteine residues that are not at the N-terminus. A substrate peptide of the Zika virus NS2B-NS3 protease cyclized in this way produced an inhibitor of high affinity and proteolytic stability.

Biocompatible Macrocyclization between Cysteine and 2-Cyanopyridine Generates Stable Peptide Inhibitors.,Nitsche C, Onagi H, Quek JP, Otting G, Luo D, Huber T Org Lett. 2019 Jun 12. doi: 10.1021/acs.orglett.9b01545. PMID:31188009^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Nitsche C, Onagi H, Quek JP, Otting G, Luo D, Huber T. Biocompatible Macrocyclization between Cysteine and 2-Cyanopyridine Generates Stable Peptide Inhibitors. Org Lett. 2019 Jun 12. doi: 10.1021/acs.orglett.9b01545. PMID:31188009 doi:http://dx.doi.org/10.1021/acs.orglett.9b01545