6CT7

Fab of anti-a-synuclein antibody BIIB054 in complex with acetylated a-synuclein peptide (1-10)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.182 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

Development of an aggregate-selective, human-derived alpha-synuclein antibody BIIB054 that ameliorates disease phenotypes in Parkinson's disease models.

Weihofen, A.Liu, Y.Arndt, J.W.Huy, C.Quan, C.Smith, B.A.Baeriswyl, J.L.Cavegn, N.Senn, L.Su, L.Marsh, G.Auluck, P.K.Montrasio, F.Nitsch, R.M.Hirst, W.D.Cedarbaum, J.M.Pepinsky, R.B.Grimm, J.Weinreb, P.H.

(2018) Neurobiol Dis 124: 276-288

  • DOI: https://doi.org/10.1016/j.nbd.2018.10.016
  • Primary Citation of Related Structures:  
    6CT7

  • PubMed Abstract: 

    Aggregation of α-synuclein (α-syn) is neuropathologically and genetically linked to Parkinson's disease (PD). Since stereotypic cell-to-cell spreading of α-syn pathology is believed to contribute to disease progression, immunotherapy with antibodies directed against α-syn is considered a promising therapeutic approach for slowing disease progression. Here we report the identification, binding characteristics, and efficacy in PD mouse models of the human-derived α-syn antibody BIIB054, which is currently under investigation in a Phase 2 clinical trial for PD. BIIB054 was generated by screening human memory B-cell libraries from healthy elderly individuals. Epitope mapping studies conducted using peptide scanning, X-ray crystallography, and mutagenesis show that BIIB054 binds to α-syn residues 1-10. BIIB054 is highly selective for aggregated forms of α-syn with at least an 800-fold higher apparent affinity for fibrillar versus monomeric recombinant α-syn and a strong preference for human PD brain tissue. BIIB054 discriminates between monomers and oligomeric/fibrillar forms of α-syn based on high avidity for aggregates, driven by weak monovalent affinity and fast binding kinetics. In efficacy studies in three different mouse models with intracerebrally inoculated preformed α-syn fibrils, BIIB054 treatment attenuated the spreading of α-syn pathology, rescued motor impairments, and reduced the loss of dopamine transporter density in dopaminergic terminals in striatum. The preclinical data reported here provide a compelling rationale for clinical development of BIIB054 for the treatment and prevention of PD.


  • Organizational Affiliation

    Biogen, 225 Binney Street, Cambridge, MA 02142, USA; Neurimmune AG, Wagistrasse 13, 8952 Schlieren, Switzerland. Electronic address: andreas.weihofen@biogen.com.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
BIIB054 Fab light chainA [auth L],
D [auth B]
214Homo sapiensMutation(s): 0 
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
BIIB054 Fab heavy chainB [auth H],
E [auth A]
220Homo sapiensMutation(s): 0 
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  • Reference Sequence

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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
ACE-MET-ASP-VAL-PHE-MET-LYS-GLY-LEU-SER-LYSC [auth S],
F [auth T]
11Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P37840 (Homo sapiens)
Explore P37840 
Go to UniProtKB:  P37840
PHAROS:  P37840
GTEx:  ENSG00000145335 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP37840
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.182 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 72.849α = 90
b = 101.492β = 117.3
c = 73.4γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
SCALAdata scaling
MOLREPphasing

Structure Validation

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Entry History 

Deposition Data

  • Released Date: 2018-12-19 
  • Deposition Author(s): Arndt, J.W.

Revision History  (Full details and data files)

  • Version 1.0: 2018-12-19
    Type: Initial release
  • Version 1.1: 2018-12-26
    Changes: Data collection, Database references