 |
PDBsum entry 3f4z
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Viral protein
|
PDB id
|
|
|
|
3f4z
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Structural and biological mimicry of protein surface recognition by alpha/beta-Peptide foldamers.
|
|
|
Authors
|
|
W.S.Horne,
L.M.Johnson,
T.J.Ketas,
P.J.Klasse,
M.Lu,
J.P.Moore,
S.H.Gellman.
|
|
|
Ref.
|
|
Proc Natl Acad Sci U S A, 2009,
106,
14751-14756.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
|
|
|
