6AXL

Crystal structure of Fab317 complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.217 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.178 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Structural basis for antibody recognition of the NANP repeats in Plasmodium falciparum circumsporozoite protein.

Oyen, D.Torres, J.L.Wille-Reece, U.Ockenhouse, C.F.Emerling, D.Glanville, J.Volkmuth, W.Flores-Garcia, Y.Zavala, F.Ward, A.B.King, C.R.Wilson, I.A.

(2017) Proc Natl Acad Sci U S A 114: E10438-E10445

  • DOI: https://doi.org/10.1073/pnas.1715812114
  • Primary Citation of Related Structures:  
    6AXK, 6AXL

  • PubMed Abstract: 

    Acquired resistance against antimalarial drugs has further increased the need for an effective malaria vaccine. The current leading candidate, RTS,S, is a recombinant circumsporozoite protein (CSP)-based vaccine against Plasmodium falciparum that contains 19 NANP repeats followed by a thrombospondin repeat domain. Although RTS,S has undergone extensive clinical testing and has progressed through phase III clinical trials, continued efforts are underway to enhance its efficacy and duration of protection. Here, we determined that two monoclonal antibodies (mAbs 311 and 317), isolated from a recent controlled human malaria infection trial exploring a delayed fractional dose, inhibit parasite development in vivo by at least 97%. Crystal structures of antibody fragments (Fabs) 311 and 317 with an (NPNA) 3 peptide illustrate their different binding modes. Notwithstanding, one and three of the three NPNA repeats adopt similar well-defined type I β-turns with Fab311 and Fab317, respectively. Furthermore, to explore antibody binding in the context of P. falciparum CSP, we used negative-stain electron microscopy on a recombinant shortened CSP (rsCSP) construct saturated with Fabs. Both complexes display a compact rsCSP with multiple Fabs bound, with the rsCSP-Fab311 complex forming a highly organized helical structure. Together, these structural insights may aid in the design of a next-generation malaria vaccine.


  • Organizational Affiliation

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Fab317 light chainsA [auth C],
C [auth B]
214Homo sapiensMutation(s): 0 
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Fab317 heavy chainB [auth D],
D [auth A]
222Homo sapiensMutation(s): 0 
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  • Reference Sequence

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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Peptide ACE-ASN-PRO-ASN-ALA-ASN-PRO-ASN-ALA-ASN-PRO-ASN-ALA-NH2E [auth G],
F [auth I]
14Plasmodium falciparumMutation(s): 0 
UniProt
Find proteins for P02893 (Plasmodium falciparum)
Explore P02893 
Go to UniProtKB:  P02893
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UniProt GroupP02893
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.217 
  • R-Value Work: 0.175 
  • R-Value Observed: 0.178 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 82.663α = 90
b = 65.342β = 106.4
c = 99.043γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-11-22
    Type: Initial release
  • Version 1.1: 2017-12-06
    Changes: Database references
  • Version 1.2: 2017-12-13
    Changes: Database references