6pyq

From Proteopedia

Assembly of VIQKI D455(beta-L-homoaspartic acid)with human parainfluenza virus type 3 (HPIV3) fusion glycoprotein N-terminal heptad repeat domain

Structural highlights

6pyq is a 6 chain structure with sequence from Human parainfluenza 3 virus (strain NIH 47885) and Human respirovirus 3. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.79Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

FUS_PI3H4 Class I viral fusion protein. Under the current model, the protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and plasma cell membrane fusion, the heptad repeat (HR) regions assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and plasma cell membranes. Directs fusion of viral and cellular membranes leading to delivery of the nucleocapsid into the cytoplasm. This fusion is pH independent and occurs directly at the outer cell membrane. The trimer of F1-F2 (F protein) probably interacts with HN at the virion surface. Upon HN binding to its cellular receptor, the hydrophobic fusion peptide is unmasked and interacts with the cellular membrane, inducing the fusion between cell and virion membranes. Later in infection, F proteins expressed at the plasma membrane of infected cells could mediate fusion with adjacent cells to form syncytia, a cytopathic effect that could lead to tissue necrosis (By similarity).

Publication Abstract from PubMed

Partial replacement of alpha-amino acid residues with beta-amino acid residues has been established as a strategy for preserving target-engagement by helix-forming polypeptides while altering other properties. The impact of beta-residue incorporation within polypeptides that adopt less regular conformations, however, has received less attention. The C-terminal heptad repeat (HRC) domains of fusion glycoproteins from pathogenic paramyxoviruses contain a segment that must adopt an extended conformation in order to coassemble with the N-terminal heptad repeat (HRN) domain in the postfusion state and drive a merger of the viral envelope with a target cell membrane. Here, we examine the impact of single alpha-to-beta substitutions within this extended N-terminal segment of an engineered HRC peptide designated VIQKI. Stabilities of hexameric coassemblies formed with the native human parainfluenza virus 3 (HPIV3) HRN have been evaluated, the structures of five coassemblies have been determined, and antiviral efficacies have been measured. Many sites within the extended segment show functional tolerance of alpha-to-beta substitution. These results offer a basis for future development of paramyxovirus infection inhibitors with novel biological activity profiles, possibly including resistance to proteolysis.

Effects of Single alpha-to-beta Residue Replacements on Recognition of an Extended Segment in a Viral Fusion Protein.,Outlaw VK, Kreitler DF, Stelitano D, Porotto M, Moscona A, Gellman SH ACS Infect Dis. 2020 Aug 14;6(8):2017-2022. doi: 10.1021/acsinfecdis.0c00385., Epub 2020 Jul 27. PMID:32692914^[1]

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

References

↑ Outlaw VK, Kreitler DF, Stelitano D, Porotto M, Moscona A, Gellman SH. Effects of Single α-to-β Residue Replacements on Recognition of an Extended Segment in a Viral Fusion Protein. ACS Infect Dis. 2020 Aug 14;6(8):2017-2022. PMID:32692914 doi:10.1021/acsinfecdis.0c00385