4M8Q

Ontogeny of recognition specificity and functionality for the anti-HIV neutralizing antibody 4E10


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.89 Å
  • R-Value Free: 0.302 
  • R-Value Work: 0.261 
  • R-Value Observed: 0.263 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

Ontogeny of Recognition Specificity and Functionality for the Broadly Neutralizing Anti-HIV Antibody 4E10.

Finton, K.A.Friend, D.Jaffe, J.Gewe, M.Holmes, M.A.Larman, H.B.Stuart, A.Larimore, K.Greenberg, P.D.Elledge, S.J.Stamatatos, L.Strong, R.K.

(2014) PLoS Pathog 10: e1004403-e1004403

  • DOI: https://doi.org/10.1371/journal.ppat.1004403
  • Primary Citation of Related Structures:  
    4LRN, 4M62, 4M8Q, 4OB5, 4ODX

  • PubMed Abstract: 

    The process of antibody ontogeny typically improves affinity, on-rate, and thermostability, narrows polyspecificity, and rigidifies the combining site to the conformer optimal for binding from the broader ensemble accessible to the precursor. However, many broadly-neutralizing anti-HIV antibodies incorporate unusual structural elements and recognition specificities or properties that often lead to autoreactivity. The ontogeny of 4E10, an autoreactive antibody with unexpected combining site flexibility, was delineated through structural and biophysical comparisons of the mature antibody with multiple potential precursors. 4E10 gained affinity primarily by off-rate enhancement through a small number of mutations to a highly conserved recognition surface. Controverting the conventional paradigm, the combining site gained flexibility and autoreactivity during ontogeny, while losing thermostability, though polyspecificity was unaffected. Details of the recognition mechanism, including inferred global effects due to 4E10 binding, suggest that neutralization by 4E10 may involve mechanisms beyond simply binding, also requiring the ability of the antibody to induce conformational changes distant from its binding site. 4E10 is, therefore, unlikely to be re-elicited by conventional vaccination strategies.


  • Organizational Affiliation

    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
GEP1 Fv heavy chainA,
D [auth H]
129Homo sapiensMutation(s): 0 
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
GEP1 Fv light chainB,
E [auth L]
113Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P01619 (Homo sapiens)
Explore P01619 
Go to UniProtKB:  P01619
PHAROS:  P01619
GTEx:  ENSG00000239951 
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UniProt GroupP01619
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
4E10 epitope scaffold T117C,
F [auth S]
161synthetic constructMutation(s): 0 
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Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.89 Å
  • R-Value Free: 0.302 
  • R-Value Work: 0.261 
  • R-Value Observed: 0.263 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 72.561α = 90
b = 77.674β = 112.03
c = 77.823γ = 90
Software Package:
Software NamePurpose
CrystalCleardata collection
PHASERphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-10-08
    Type: Initial release
  • Version 1.1: 2018-03-07
    Changes: Data collection