PDBsum entry 3f4z

Viral protein

PDB id: 3f4z

Contents

Protein chains

39 a.a.

34 a.a.

40 a.a.

Ligands

MPD ×8

Waters ×201

PDB id:

3f4z

Name:

Viral protein

Title:

Trimeric helix bundle formed by an alpha/beta-peptide derivative of the HIV gp41 chr domain

Structure:

Alpha/beta-peptide analogue of the HIV gp41 chr domain. Chain: a, b, c. Engineered: yes

Source:

Synthetic: yes. Other_details: the peptide is chemically synthesized. It is a sequence mutant to a sequence that occurs naturally in HIV.

Resolution:

2.10Å R-factor: 0.206 R-free: 0.249

Authors:

W.S.Horne,S.H.Gellman

Key ref:

W.S.Horne et al. (2009). Structural and biological mimicry of protein surface recognition by alpha/beta-peptide foldamers. Proc Natl Acad Sci U S A, 106, 14751-14756. PubMed id: 19706443 DOI: 10.1073/pnas.0902663106

Date:

03-Nov-08 Release date: 15-Sep-09

Protein chain

No UniProt id for this chain

Struc: 38 a.a.

Protein chain

No UniProt id for this chain

Struc: 34 a.a.

Protein chain

No UniProt id for this chain

Struc: 39 a.a.

DOI no: 10.1073/pnas.0902663106

Proc Natl Acad Sci U S A 106:14751-14756 (2009)

PubMed id: 19706443

Structural and biological mimicry of protein surface recognition by alpha/beta-peptide foldamers.

W.S.Horne, L.M.Johnson, T.J.Ketas, P.J.Klasse, M.Lu, J.P.Moore, S.H.Gellman.

ABSTRACT

Unnatural oligomers that can mimic protein surfaces offer a potentially useful strategy for blocking biomedically important protein-protein interactions. Here we evaluate an approach based on combining alpha- and beta-amino acid residues in the context of a polypeptide sequence from the HIV protein gp41, which represents an excellent testbed because of the wealth of available structural and biological information. We show that alpha/beta-peptides can mimic structural and functional properties of a critical gp41 subunit. Physical studies in solution, crystallographic data, and results from cell-fusion and virus-infectivity assays collectively indicate that the gp41-mimetic alpha/beta-peptides effectively block HIV-cell fusion via a mechanism comparable to that of gp41-derived alpha-peptides. An optimized alpha/beta-peptide is far less susceptible to proteolytic degradation than is an analogous alpha-peptide. Our findings show how a two-stage design approach, in which sequence-based alpha-->beta replacements are followed by site-specific backbone rigidification, can lead to physical and biological mimicry of a natural biorecognition process.

Selected figure(s)

Figure 1.
Structures of the α-peptides and α/β-peptides derived from HIV gp41 used in this study. (A) Structures of an α-amino acid residue, the corresponding β^3-residue analogue, and cyclic β-residues ACPC and APC. (B) Primary sequences of α-peptides 1–3 and α/β-peptides 4–11. Colored circles indicate β-residues.

Figure 3.
Crystal structures of the six-helix bundles formed by NHR α-peptide 1 in complex with α-peptide 3, α/β-peptide 10, or chimeric α/β-peptide 8. (A) Views from the side and looking down the superhelical axis of the indicated six-helix bundles. NHR helices are colored gray, CHR helices are colored by residue type (yellow for α, cyan for β^3, and red for cyclic β). (B) Overlay of the all α-peptide helix bundle formed 1+3 with that formed by 1+10 or 1+8. The CHR helix from 1+3 is colored green; otherwise, coloring is the same as in A. In A and B, the structures viewed from the side are oriented with the CHR N terminus at the top of the page; the structures viewed down the superhelical axis are oriented with the CHR N terminus projecting out of the page. (C) Packing interactions of CHR residues Trp[3], Trp[6], and Ile[10] (shown as sticks) against the NHR core trimer (shown as surface) in the structures of 1+3, 1+10, and 1+8; in the structure of 1+10, neither Trp[3] nor Trp[6] was resolved in electron density past C[β], and a molecule of glycerol (shown as sticks) was observed in the Trp[6] binding cavity. Coloring is the same as in A.

Figures were selected by an automated process.