6DB5

Crystal structure of anti-HIV-1 V3 Fab TA6 in complex with a HIV-1 gp120 V3 peptide from NY5 strain


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.283 
  • R-Value Work: 0.227 
  • R-Value Observed: 0.230 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Structural Comparison of Human Anti-HIV-1 gp120 V3 Monoclonal Antibodies of the Same Gene Usage Induced by Vaccination and Chronic Infection.

Chan, K.W.Pan, R.Costa, M.Gorny, M.K.Wang, S.Lu, S.Kong, X.P.

(2018) J Virol 92

  • DOI: https://doi.org/10.1128/JVI.00641-18
  • Primary Citation of Related Structures:  
    6DB5, 6DB6, 6DB7

  • PubMed Abstract: 

    Elucidating the structural basis of antibody (Ab) gene usage and affinity maturation of vaccine-induced Abs can inform the design of immunogens for inducing desired Ab responses in HIV vaccine development. Analyses of monoclonal Abs (MAbs) encoded by the same immunoglobulin genes at different stages of maturation can help to elucidate the maturation process. We have analyzed four human anti-V3 MAbs with the same VH1-3*01 and VL3-10*01 gene usage. Two MAbs, TA6 and TA7, were developed from a vaccinee in the HIV vaccine phase I trial DP6-001 with a polyvalent DNA prime/protein boost regimen, and two others, 311-11D and 1334, were developed from HIV-infected patients. The somatic hypermutation (SHM) rates in VH of vaccine-induced MAbs are lower than in chronic HIV infection-induced MAbs, while those in VL are comparable. Crystal structures of the antigen-binding fragments (Fabs) in complex with V3 peptides show that these MAbs bind the V3 epitope with a new cradle-binding mode and that the V3 β-hairpin lies along the antigen-binding groove, which consists of residues from both heavy and light chains. Residues conserved from the germ line sequences form specific binding pockets accommodating conserved structural elements of the V3 crown hairpin, predetermining the Ab gene selection, while somatically mutated residues create additional hydrogen bonds, electrostatic interactions, and van der Waals contacts, correlating with an increased binding affinity. Our data provide a unique example of germ line sequences determining the primordial antigen-binding sites and SHMs correlating with affinity maturation of Abs induced by vaccine and natural HIV infection. IMPORTANCE Understanding the structural basis of gene usage and affinity maturation for anti-HIV-1 antibodies may help vaccine design and development. Antibodies targeting the highly immunogenic third variable loop (V3) of HIV-1 gp120 provide a unique opportunity for detailed structural investigations. By comparing the sequences and structures of four anti-V3 MAbs at different stages of affinity maturation but of the same V gene usage, two induced by vaccination and another two by chronic infection, we provide a fine example of how germ line sequence determines the essential elements for epitope recognition and how affinity maturation improves the antibody's recognition of its epitope.


  • 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
Human monoclonal anti-HIV-1 gp120 V3 antibody TA6 Fab heavy chainA [auth H],
D [auth I]
232Homo sapiensMutation(s): 0 
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Human monoclonal anti-HIV-1 gp120 V3 antibody TA6 Fab light chainB [auth L],
E [auth M]
214Homo sapiensMutation(s): 0 
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  • Reference Sequence

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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
HIV-1 gp120 V3 peptide from NY5 strainC [auth P],
F [auth Q]
20Human immunodeficiency virus 1Mutation(s): 0 
UniProt
Find proteins for P12490 (Human immunodeficiency virus type 1 group M subtype B (isolate NY5))
Explore P12490 
Go to UniProtKB:  P12490
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP12490
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.283 
  • R-Value Work: 0.227 
  • R-Value Observed: 0.230 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 78.616α = 90
b = 67.361β = 100.25
c = 103.038γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
PHASERphasing
XDSdata scaling
Cootmodel building

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 StatesAI100151
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United StatesAI082676
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United StatesAI082274
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United StatesAI087191
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United StatesAI112546

Revision History  (Full details and data files)

  • Version 1.0: 2018-07-11
    Type: Initial release
  • Version 1.1: 2018-07-25
    Changes: Data collection, Database references
  • Version 1.2: 2018-09-12
    Changes: Data collection, Database references
  • Version 1.3: 2019-12-18
    Changes: Author supporting evidence