PDBsum entry 2q7c

Viral protein

PDB id: 2q7c

Contents

Protein chains

46 a.a.

Metals

_CL ×4

Waters ×84

PDB id:

2q7c

Name:

Viral protein

Title:

Crystal structure of iqn17

Structure:

Fusion protein between yeast variant gcn4 and hivgp41. Chain: a, b, c. Synonym: iqn17. Engineered: yes

Source:

Synthetic: yes. Other_details: synthetic peptide. The sequence naturally occurs in saccharomyces cerevisiae and human immunodeficiency virus.

Resolution:

2.00Å R-factor: 0.238 R-free: 0.310

Authors:

V.N.Malashkevich,D.M.Eckert,L.H.Hong,P.S.Kim

Key ref:

D.M.Eckert et al. (1999). Inhibiting HIV-1 entry: discovery of D-peptide inhibitors that target the gp41 coiled-coil pocket. Cell, 99, 103-115. PubMed id: 10520998 DOI: 10.1016/S0092-8674(00)80066-5

Date:

06-Jun-07 Release date: 19-Jun-07

Protein chains

A3F986  (A3F986_HV1) -  Envelope glycoprotein gp160 from Human immunodeficiency virus type 1

Seq: 858 a.a.

Struc: 45 a.a.*

* PDB and UniProt seqs differ at 23 residue positions (black crosses)

DOI no: 10.1016/S0092-8674(00)80066-5

Cell 99:103-115 (1999)

PubMed id: 10520998

Inhibiting HIV-1 entry: discovery of D-peptide inhibitors that target the gp41 coiled-coil pocket.

D.M.Eckert, V.N.Malashkevich, L.H.Hong, P.A.Carr, P.S.Kim.

ABSTRACT

The HIV-1 gp41 protein promotes viral entry by mediating the fusion of viral and cellular membranes. A prominent pocket on the surface of a central trimeric coiled coil within gp41 was previously identified as a potential target for drugs that inhibit HIV-1 entry. We designed a peptide, IQN17, which properly presents this pocket. Utilizing IQN17 and mirror-image phage display, we identified cyclic, D-peptide inhibitors of HIV-1 infection that share a sequence motif. A 1.5 A cocrystal structure of IQN17 in complex with a D-peptide, and NMR studies, show that conserved residues of these inhibitors make intimate contact with the gp41 pocket. Our studies validate the pocket per se as a target for drug development. IQN17 and these D-peptide inhibitors are likely to be useful for development and identification of a new class of orally bioavailable anti-HIV drugs.

Selected figure(s)

Figure 1.
Figure 1. Model of HIV Membrane Fusion and Structure of the gp41 CoreSchematic representation of a working model for HIV membrane fusion (for review[9]). In the native state of the trimeric gp120/gp41 complex (“Native”), the fusion peptide and N-peptide regions of gp41 are not exposed. Following interaction with cellular receptors (CD4 and coreceptor), a conformational change results in formation of the transient prehairpin intermediate (“Pre-Hairpin”), in which the fusion peptide regions (red lines) are inserted into the cell membrane and the coiled coil of the N-peptide region of gp41 (indicated as “N”) is exposed. However, the C-peptide region of gp41 (indicated as “C”) is constrained and unavailable for interaction with the coiled coil. Thus, exogenous C-peptides can bind to the prehairpin intermediate and inhibit fusion in a dominant-negative manner (“Inhibited”). In the absence of inhibitors, the prehairpin intermediate resolves to the hairpin structure and membrane fusion results (“Hairpin/Fusion”), although it is not known whether hairpin formation precedes membrane fusion per se. The C-peptides discussed in this paper (and corresponding residues in gp41, numbered according to their position in gp160 of the HXB2 HIV-1 strain) are as follows: C34 [628–661]; DP178, also called T-20 [638–673]; and T649 [628–663]. Adapted from [9].The inset depicts the 2.0 Å X-ray crystal structure of N36/C34, a peptide version of the HIV-1 gp41 core ([10]). Three central N-peptides form a coiled coil, shown here as a surface representation, and three helical C-peptides pack along conserved grooves on the surface of the coiled-coil trimer. There are three symmetry-related hydrophobic pockets on the surface of the N-peptide coiled coil (shaded). The pocket region is highly conserved among HIV-1 isolates. There are 11 residues that comprise the lining of the hydrophobic pocket (see Figure 7 of [10]): Leu-565, Leu-566, Leu-568, Thr-569, Val-570, Trp-571, Gly-572, Ile-573, Lys-574, Leu-576, and Gln-577 of HXB2. These 11 residues are completely conserved in 158 of 202 fully sequenced M group HIV-1 strains (HIV Sequence Database [1998/1999 alignments], Los Alamos National Laboratory, ). Of the remaining 44 isolates, 33 possess only a single conservative methionine substitution for Leu-565.

Figure 5.
Figure 5. Crystal Structure of a D-Peptide Bound to the gp41 Pocket(A) Ribbon representation of the overall structure of the IQN17/D10-p1 complex. The GCN4-pI[Q]I′ part of the chimera (dark blue) and the HIV-1 gp41 hydrophobic segment (gray) form a continuous three-stranded coiled coil. Three D10-p1 inhibitors (purple and green) bind solely to the hydrophobic pocket. The six residues of the D-peptide that make direct contact with IQN17 are shown in green (Gly-1, Ala-2, Trp-10, Trp-12, Leu-13, and Ala-16). Figure drawn with Insight II 98.0 (Molecular Simulations Inc.).(B) Stereo view of the IQN17/D10-p1 complex in which IQN17 is represented as a molecular surface and D10-p1 is represented with sticks. The color scheme is as in (A). The four conserved residues of the EWXWL motif (Glu-9, Trp-10, Trp-12, and Leu-13) are labeled. Figure drawn with Insight II 98.0 (Molecular Simulations Inc.).(C) Stereo view of a region of the final 1.5 Å 2Fo-Fc map, contoured at 2.1σ, superimposed on the final model. The view is approximately the same orientation as in (B). Figure drawn with O ([26]).

The above figures are reprinted by permission from Cell Press: Cell (1999, 99, 103-115) copyright 1999.

Figures were selected by an automated process.