5X08

Crystal structure of broadly neutralizing anti-HIV-1 antibody 4E10, mutant Npro, with peptide bound


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.49 Å
  • R-Value Free: 0.169 
  • R-Value Work: 0.129 
  • R-Value Observed: 0.130 

wwPDB Validation   3D Report Full Report


This is version 1.6 of the entry. See complete history


Literature

Functional Contacts between MPER and the Anti-HIV-1 Broadly Neutralizing Antibody 4E10 Extend into the Core of the Membrane

Rujas, E.Insausti, S.Garcia-Porras, M.Sanchez-Eugenia, R.Tsumoto, K.Nieva, J.L.Caaveiro, J.M.M.

(2017) J Mol Biol 429: 1213-1226

  • DOI: https://doi.org/10.1016/j.jmb.2017.03.008
  • Primary Citation of Related Structures:  
    5X08

  • PubMed Abstract: 

    The exceptional breadth of broadly neutralizing antibodies (bNAbs) against the membrane-proximal external region (MPER) of the transmembrane protein gp41 makes this class of antibodies an ideal model to design HIV vaccines. From a practical point of view, however, the preparation of vaccines eliciting bNAbs is still a major roadblock that limits their clinical application. Fresh mechanistic insights are necessary to develop more effective strategies. In particular, the function of the unusually long complementarity-determining region three of the heavy chain (CDRH3) of 4E10, an anti-MPER bNAb, is an open question that fascinates researchers in the field. Residues comprising the apex region are dispensable for engagement of the epitope in solution; still, their single mutation profoundly impairs the neutralization capabilities of the antibody. Since this region is very hydrophobic, it has been proposed that the apex is essential for anchoring the antibody to the viral membrane where MPER resides. Herein, we have critically examined this idea using structural, biophysical, biochemical, and cell-based approaches. Our results demonstrate that the apex region is not just a "greasy" spot merely increasing the affinity of the antibody for the membrane. We demonstrate the three-dimensional engagement of the apex region of the CDRH3 with the conglomerate of gp41 epitope and membrane lipids as a means of effective binding and neutralization of the virus. This mechanism of recognition suggests a standard route of antibody ontogeny. Therefore, we need to focus our efforts on recreating a more realistic MPER/lipid immunogen in order to generate more effective anti-HIV-1 vaccines.


  • Organizational Affiliation

    Biofisika Institute (CSIC, UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country, P.O. Box 644, Bilbao 48080, Spain; Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Bunkyo-ku, Tokyo 113-8656, Japan.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Fab 4E10 Heavy chainA [auth H]230Homo sapiensMutation(s): 0 
Gene Names: IgG1
Entity Groups  
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Fab 4E10 Light chainB [auth L]214Homo sapiensMutation(s): 0 
Gene Names: IgG1
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  • Reference Sequence

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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Envelope glycoprotein gp160C [auth P]16Human immunodeficiency virus type 1 (MAL ISOLATE)Mutation(s): 0 
Gene Names: ENV
UniProt
Find proteins for P04578 (Human immunodeficiency virus type 1 group M subtype B (isolate HXB2))
Explore P04578 
Go to UniProtKB:  P04578
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04578
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
P6G
Query on P6G

Download Ideal Coordinates CCD File 
G [auth L]HEXAETHYLENE GLYCOL
C12 H26 O7
IIRDTKBZINWQAW-UHFFFAOYSA-N
PGE
Query on PGE

Download Ideal Coordinates CCD File 
E [auth H]TRIETHYLENE GLYCOL
C6 H14 O4
ZIBGPFATKBEMQZ-UHFFFAOYSA-N
GOL
Query on GOL

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D [auth H],
F [auth L]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ACT
Query on ACT

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I [auth P]ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
CL
Query on CL

Download Ideal Coordinates CCD File 
H [auth L]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.49 Å
  • R-Value Free: 0.169 
  • R-Value Work: 0.129 
  • R-Value Observed: 0.130 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 157.509α = 90
b = 44.5β = 113.7
c = 85.13γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
JSPSJapan15K06962
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United StatesAI097051
Basque GovernmentSpainIT838-13
JSPSJapan25249115
JSPSJapan16H02420
MEXTJapanPlatform for Drug Discovery

Revision History  (Full details and data files)

  • Version 1.0: 2017-04-05
    Type: Initial release
  • Version 1.1: 2017-04-26
    Changes: Database references
  • Version 1.2: 2017-08-30
    Changes: Data collection
  • Version 1.3: 2017-10-18
    Changes: Author supporting evidence
  • Version 1.4: 2018-06-20
    Changes: Data collection, Database references
  • Version 1.5: 2022-03-23
    Changes: Author supporting evidence, Database references
  • Version 1.6: 2023-11-22
    Changes: Data collection, Refinement description