PDBsum entry 1yyl

Viral protein/immune system

PDB id: 1yyl

Contents

Protein chains

301 a.a. *

214 a.a. *

229 a.a. *

27 a.a. *

Ligands

NAG ×16

Waters ×324

* Residue conservation analysis

PDB id:

1yyl

Name:

Viral protein/immune system

Title:

Crystal structure of cd4m33, a scorpion-toxin mimic of cd4, in complex with HIV-1 yu2 gp120 envelope glycoprotein and anti-HIV-1 antibody 17b

Structure:

Exterior membrane glycoprotein(gp120),exterior membrane glycoprotein(gp120),exterior membrane glycoprotein(gp120). Chain: g, p. Fragment: unp residues 82-126,unp residues 191-293,unp residues 325- 479. Synonym: HIV-1 yu2 gp120, envelope glycoprotein gp160,HIV-1 yu2 gp120, envelope glycoprotein gp160,HIV-1 yu2 gp120, envelope glycoprotein gp160. Engineered: yes.

Source:

Human immunodeficiency virus 1. Organism_taxid: 11676. Expressed in: drosophila melanogaster. Expression_system_taxid: 7227. Homo sapiens. Human. Organism_taxid: 9606. Expressed in: mus musculus. Expression_system_taxid: 10090.

Biol. unit:

Dimer (from PQS)

Resolution:

2.75Å R-factor: 0.202 R-free: 0.275

Authors:

C.C.Huang,F.Stricher,L.Martin,J.M.Decker,S.Majeed,P.Barthe, W.A.Hendrickson,J.Robinson,C.Roumestand,J.Sodroski,R.Wyatt,G.M.Shaw, C.Vita,P.D.Kwong

Key ref:

C.C.Huang et al. (2005). Scorpion-toxin mimics of CD4 in complex with human immunodeficiency virus gp120 crystal structures, molecular mimicry, and neutralization breadth. Structure, 13, 755-768. PubMed id: 15893666 DOI: 10.1016/j.str.2005.03.006

Date:

25-Feb-05 Release date: 03-May-05

Protein chains

P35961  (ENV_HV1Y2) -  Envelope glycoprotein gp160 from Human immunodeficiency virus type 1 group M subtype B (isolate YU-2)

Seq: 843 a.a.

Struc: 301 a.a.*

Protein chains

No UniProt id for this chain

Struc: 214 a.a.

Protein chains

No UniProt id for this chain

Struc: 229 a.a.

Protein chains

No UniProt id for this chain

Struc: 27 a.a.

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

DOI no: 10.1016/j.str.2005.03.006

Structure 13:755-768 (2005)

PubMed id: 15893666

Scorpion-toxin mimics of CD4 in complex with human immunodeficiency virus gp120 crystal structures, molecular mimicry, and neutralization breadth.

C.C.Huang, F.Stricher, L.Martin, J.M.Decker, S.Majeed, P.Barthe, W.A.Hendrickson, J.Robinson, C.Roumestand, J.Sodroski, R.Wyatt, G.M.Shaw, C.Vita, P.D.Kwong.

ABSTRACT

The binding surface on CD4 for the HIV-1 gp120 envelope glycoprotein has been transplanted previously onto a scorpion-toxin scaffold. Here, we use X-ray crystallography to characterize atomic-level details of gp120 with this transplant, CD4M33. Despite known envelope flexibility, the conformation of gp120 induced by CD4M33 was so similar to that induced by CD4 that localized measures were required to distinguish ligand-induced differences from lattice variation. To investigate relationships between structure, function, and mimicry, an F23 analog of CD4M33 was devised. Structural and thermodynamic analyses showed F23 to be a better molecular mimic of CD4 than CD4M33. F23 also showed increased neutralization breadth, against diverse isolates of HIV-1, HIV-2, and SIVcpz. Our results lend insight into the stability of the CD4 bound conformation of gp120, define measures that quantify molecular mimicry as a function of evolutionary distance, and suggest how such evaluations might be useful in developing mimetic antagonists with increased neutralization breadth.

Selected figure(s)

Figure 1.
Figure 1. Mimicry of CD4 by CD4M33
(A) Ribbon diagrams of core YU2 gp120 (green) are shown binding to CD4 (left) and CD4M33 (right). In this orientation, the four-stranded bridging sheet of gp120 is positioned directly to the left of CD4, the inner domain is positioned above it, and the outer domain is positioned to the right. CD4M33 is shown in purple, and CD4 is shown in gray, except for the three main regions that contribute to binding, which are colored orange-yellow (residues 40-48) and black (residues 31-35 and 58-64).
(B) Close-up view of the CD4-gp120 "hotspot." The orientation and colors are the same as in (A), except that oxygen atoms are colored red and nitrogen atoms are colored blue. The unusual interfacial cavity (red) between CD4 and gp120 is shown in the left panel. The right panel shows the biphenyl side chain of CD4M33 reaching into the heart of gp120. Density (F[o] - F[c]; 3 s; purple) is shown from a simulated annealing omit map in which the entire CD4M33 had been removed. Distances (Å) are shown for four hydrogen bonds.
(C) Close-up view of an intermolecular salt bridge. The left panel shows the double hydrogen bond made by CD4 Arg 59. The right panel displays the two independent CD4M33 complexes of the P2[1] asymmetric unit (purple and gray), only one of which makes a salt bridge with gp120.
(D) Contact surface on gp120. The orientation shown is rotated 90° about a horizontal axis from that shown in (A) and (B). In this orientation, the virus would be located toward the top of the page, and the target cell would be located toward the bottom. The left panel shows the contact surface of CD4, colored green, with yellow highlighting the portion of the surface contacted by CD4 residues 40-47. The right panel shows the contact surface of CD4M33 in green, with purple highlighting the portion of the surface contributed by CD4M33 residues 20-27. The portion of the contact surface unique to CD4M33 (primarily where the biphenyl moiety reaches into gp120) is highlighted in red.

The above figure is reprinted by permission from Cell Press: Structure (2005, 13, 755-768) copyright 2005.

Figure was selected by an automated process.