PDBsum entry 1g2c

Viral protein

PDB id: 1g2c

Contents

Protein chains

50 a.a. *

40 a.a. *

36 a.a. *

37 a.a. *

50 a.a. *

40 a.a. *

47 a.a. *

50 a.a. *

38 a.a. *

Waters ×888

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Structural characterization of the human respiratory syncytial virus fusion protein core.

Authors

X.Zhao, M.Singh, V.N.Malashkevich, P.S.Kim.

Ref.

Proc Natl Acad Sci U S A, 2000, 97, 14172-14177. [DOI no: 10.1073/pnas.260499197]

PubMed id

11106388

Abstract

Human respiratory syncytial virus (HRSV) is a major cause of a number of severe respiratory diseases, including bronchiolitis and pneumonia, in infants and young children. The HRSV F protein, a glycoprotein essential for viral entry, is a primary target for vaccine and drug development. Two heptad-repeat regions within the HRSV F sequence were predicted by the computer program learncoil-vmf. These regions are thought to form trimer-of-hairpins-like structures, similar to those found in the fusion proteins of several enveloped viruses. The hairpin structure likely brings the viral and cellular membranes into close apposition, thereby facilitating membrane fusion and subsequent viral entry. Here, we show that peptides, denoted HR-N and HR-C, corresponding to the heptad-repeat regions from the N-terminal and C-terminal segments of the HRSV F protein, respectively, form a stable alpha-helical trimer of heterodimers. The HRSV N/C complex was crystallized and its x-ray structure was determined at 2.3-A resolution. As anticipated, the complex is a six-helix bundle in which the HR-N peptides form a three-stranded, central coiled coil, and the HR-C peptides pack in an antiparallel manner into hydrophobic grooves on the coiled-coil surface. There is remarkable structural similarity between the HRSV N/C complex and the fusion protein core of other viruses, including HIV-1 gp41. In addition, earlier work has shown that HRSV HR-C peptides, like the HIV-1 gp41 C peptides, inhibit viral infection. Thus, drug discovery and vaccine development strategies aimed at inhibiting viral entry by blocking hairpin formation may be applied to the inhibition of HRSV.

Figure 1.
Fig. 1. Schematic diagram of the HRSV F protein sequence. F1 and F2 are formed after proteolytic cleavage of the precursor F0. The signal peptide (SP), the cleavage site (CS), the putative fusion peptide (FP), the N-terminal HR (HR-N) region, the C-terminal HR (HR-C) region, and the transmembrane segment (TM) within the amino acid sequence of the recombinant recRSV-1 construct are indicated. The HR-N and HR-C regions predicted by LEARNCOIL-VMF are represented by shaded boxes. Protease-resistant fragments from trypsin (HRSV-N57 and HRSV-C45) and proteinase K (HRSV-N51 and HRSV-C39) cleavage are indicated.

Figure 6.
Fig. 6. The cavity on the surface of the HRSV-N57 coiled coil. (A) A stereo view of interactions in the HRSV-N57 cavity. Two phenylalanine residues of HRSV-C45 (yellow) fit into the cavity formed by two neighboring HRSV-N57 peptides (blue). A prime symbol is used to distinguish residues from the two HRSV-N57 chains. Figure was prepared with MOLSCRIPT (45). (B) Comparison of cavity interactions of the HRSV and SV5 structures. The HRSV-N57 coiled coils, which superimpose closely with the SV5 N peptide coiled coils (21), are represented as a molecular surface (the most convex part shown in green and the most concave in gray). The HRSV-C45 (yellow) and SV5 C peptide (pink) helices are shown as ribbons with selected side chains that pack into the cavity. The relative shift of the C peptides is clearly visible. Figure was drawn with the program GRASP (46).