5V6L

Crystal Structure of Rabbit Anti-HIV-1 gp120 V3 Fab 10A37 in complex with V3 peptide JR-FL


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.55 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.208 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Increased epitope complexity correlated with antibody affinity maturation and a novel binding mode revealed by structures of rabbit antibodies against the third variable loop (V3) of HIV-1 gp120.

Pan, R.Qin, Y.Banasik, M.Lees, W.Shepherd, A.J.Cho, M.W.Kong, X.P.

(2018) J Virol 

  • DOI: https://doi.org/10.1128/JVI.01894-17
  • Primary Citation of Related Structures:  
    5V6L, 5V6M

  • PubMed Abstract: 

    The third variable (V3) loop of HIV-1 gp120 is an immunodominant region targeted by neutralizing antibodies (nAbs). Despite limited breadth, better characterization of the structural details of the interactions between these nAbs and their target epitopes would enhance our understanding of the mechanism of neutralization and facilitate designing better immunogens to induce nAbs with greater breadth. Recently, we isolated two anti-V3 neutralizing monoclonal antibodies (MAbs), 10A3 and 10A37, from a rabbit immunized with gp120 of the M group consensus sequence. In this study, crystal structures of these MAbs bound to target epitopes were determined. 10A3 binds to the V3 crown ( 303 TRKSIHIGPGRAF 317 ) using the cradle binding mode, similar to human V3 MAbs encoded by IGHV5-51 germ line genes, and its epitope structure resembles that bound to the human antibodies. In contrast, 10A37, which exhibits greater breadth and potency than 10A3, binds the V3 crown and the succeeding stem region ( 308 HIGPGRAFYTTGEI 323 ). Unexpectedly, the 315 RAFYTT 320 portion of the epitope existed as helical turns, a V3 structure that has not been observed previously. Its main chain-dominated antigen-antibody interactions not only explain the broad neutralization of 10A37 but also show that its epitope is a potential vaccine target to be further evaluated. In conclusion, our study provides novel insights about neutralization-susceptible epitope structures of the V3 loop of HIV-1 gp120 and demonstrates that, despite low amino acid sequence similarity to human antibody germ line genes, rabbits can serve as a useful animal model to evaluate human vaccine candidates. IMPORTANCE The apex crown of V3 of HIV-1 gp120 is the most immunogenic region of the surface glycoprotein, and many MAbs targeting this region have been developed. Structural understanding of V3 crown MAbs not only can help understand how antibody responses target this unique region but also contribute to immunogen design for vaccine development. We present here crystal structures of two neutralizing V3 MAbs, 10A3 and 10A37, developed from a rabbit immunized with gp120. Our analysis of 10A3 in complex with V3 provided a detailed example of how epitope complexity can evolve with affinity maturation, while that of 10A37 revealed a novel V3 binding mode targeting the C-terminal side of the V3 crown and showed that this region can form a helical structure. Our study provides novel insights about neutralization-susceptible V3 epitope structures and demonstrates that rabbits can serve as a useful animal model to evaluate human vaccine candidates.


  • Organizational Affiliation

    Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, New York, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Light chain of Fab fragment of rabbit anti-HIV1 gp120 V3 mAb 10A37A [auth L],
D [auth M]
215Oryctolagus cuniculusMutation(s): 0 
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Heavy chain of Fab fragment of rabbit anti-HIV1 gp120 V3 mAb 10A37B [auth H],
E [auth I]
220Oryctolagus cuniculusMutation(s): 0 
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  • Reference Sequence

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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Envelope glycoprotein, v3 regionC [auth P],
F [auth Q]
23Human immunodeficiency virus 1Mutation(s): 0 
UniProt
Find proteins for P20871 (Human immunodeficiency virus type 1 group M subtype B (isolate JRCSF))
Explore P20871 
Go to UniProtKB:  P20871
Entity Groups  
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UniProt GroupP20871
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.55 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.208 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 43.234α = 90
b = 173.904β = 99.98
c = 70.912γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
PHENIXmodel building
PHENIXphasing
XDSdata scaling

Structure Validation

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Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United StatesAI074286
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United StatesAI100151

Revision History  (Full details and data files)

  • Version 1.0: 2018-01-17
    Type: Initial release
  • Version 1.1: 2018-01-31
    Changes: Database references
  • Version 1.2: 2019-12-11
    Changes: Author supporting evidence
  • Version 1.3: 2023-10-04
    Changes: Data collection, Database references, Refinement description