2I60

Crystal structure of [Phe23]M47, a scorpion-toxin mimic of CD4, in complex with HIV-1 YU2 GP120 envelope glycoprotein and anti-HIV-1 antibody 17B


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.281 
  • R-Value Work: 0.215 
  • R-Value Observed: 0.215 

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Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Combinatorial optimization of a CD4-mimetic miniprotein and cocrystal structures with HIV-1 gp120 envelope glycoprotein.

Stricher, F.Huang, C.C.Descours, A.Duquesnoy, S.Combes, O.Decker, J.M.Kwon, Y.D.Lusso, P.Shaw, G.M.Vita, C.Kwong, P.D.Martin, L.

(2008) J Mol Biol 382: 510-524

  • DOI: https://doi.org/10.1016/j.jmb.2008.06.069
  • Primary Citation of Related Structures:  
    2I5Y, 2I60

  • PubMed Abstract: 

    Miniproteins provide a bridge between proteins and small molecules. Here we adapt methods from combinatorial chemistry to optimize CD4M33, a synthetic miniprotein into which we had previously transplanted the HIV-1 gp120 binding surface of the CD4 receptor. Iterative deconvolution of generated libraries produced CD4M47, a derivative of CD4M33 that had been optimized at four positions. Surface plasmon resonance demonstrated fourfold to sixfold improvement in CD4M47 affinity for gp120 to a level about threefold tighter than that of CD4 itself. Assessment of the neutralization properties of CD4M47 against a diverse range of isolates spanning from HIV-1 to SIVcpz showed that CD4M47 retained the extraordinary breadth of the parent CD4M33, but yielded only limited improvements in neutralization potencies. Crystal structures of CD4M47 and a phenylalanine variant ([Phe23]M47) were determined at resolutions of 2.4 and 2.6 A, in ternary complexes with HIV-1 gp120 and the 17b antibody. Analysis of these structures revealed a correlation between mimetic affinity for gp120 and overall mimetic-gp120 interactive surface. A correlation was also observed between CD4- and mimetic-induced gp120 structural similarity and CD4- and mimetic-induced gp120 affinity for the CCR5 coreceptor. Despite mimetic substitutions, including a glycine-to-(d)-proline change, the gp120 conformation induced by CD4M47 was as close or closer to the conformation induced by CD4 as the one induced by the parent CD4M33. Our results demonstrate the ability of combinatorial chemistry to optimize a disulfide-containing miniprotein, and of structural biology to decipher the resultant interplay between binding affinity, neutralization breadth, molecular mimicry, and induced affinity for CCR5.


  • Organizational Affiliation

    CEA, iBiTecS, SIMOPRO, Gif-sur-Yvette F-91191, France.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
EXTERIOR MEMBRANE GLYCOPROTEIN(GP120)A [auth G],
E [auth P]
313Human immunodeficiency virus 1Mutation(s): 0 
Gene Names: Env
UniProt
Find proteins for P35961 (Human immunodeficiency virus type 1 group M subtype B (isolate YU-2))
Explore P35961 
Go to UniProtKB:  P35961
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP35961
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
ANTIBODY 17B LIGHT CHAINB [auth L],
F [auth Q]
214Homo sapiensMutation(s): 0 
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
ANTIBODY 17B HEAVY CHAINC [auth H],
G [auth R]
229Homo sapiensMutation(s): 0 
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
[PHE23]M47, SCORPION-TOXIN MIMIC OF CD4D [auth M],
H [auth S]
27synthetic constructMutation(s): 0 
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  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAG
Query on NAG

Download Ideal Coordinates CCD File 
I [auth G]
J [auth G]
K [auth G]
L [auth G]
M [auth G]
I [auth G],
J [auth G],
K [auth G],
L [auth G],
M [auth G],
N [auth G],
O [auth G],
P [auth G],
R [auth P],
S [auth P],
T [auth P],
U [auth P],
V [auth P],
W [auth P],
X [auth P],
Y [auth P]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
IPA
Query on IPA

Download Ideal Coordinates CCD File 
Q [auth G],
Z [auth P]
ISOPROPYL ALCOHOL
C3 H8 O
KFZMGEQAYNKOFK-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.281 
  • R-Value Work: 0.215 
  • R-Value Observed: 0.215 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 51.439α = 90
b = 157.765β = 93.74
c = 109.846γ = 90
Software Package:
Software NamePurpose
CNSrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2006-10-10
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Non-polymer description, Version format compliance
  • Version 1.3: 2012-06-06
    Changes: Structure summary
  • Version 1.4: 2017-08-16
    Changes: Source and taxonomy
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Atomic model, Data collection, Database references, Derived calculations, Non-polymer description, Structure summary
  • Version 2.1: 2023-08-30
    Changes: Data collection, Database references, Refinement description, Structure summary