5B71

Crystal structure of complement C5 in complex with SKY59


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.11 Å
  • R-Value Free: 0.285 
  • R-Value Work: 0.246 
  • R-Value Observed: 0.248 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

Long lasting neutralization of C5 by SKY59, a novel recycling antibody, is a potential therapy for complement-mediated diseases.

Fukuzawa, T.Sampei, Z.Haraya, K.Ruike, Y.Shida-Kawazoe, M.Shimizu, Y.Gan, S.W.Irie, M.Tsuboi, Y.Tai, H.Sakiyama, T.Sakamoto, A.Ishii, S.Maeda, A.Iwayanagi, Y.Shibahara, N.Shibuya, M.Nakamura, G.Nambu, T.Hayasaka, A.Mimoto, F.Okura, Y.Hori, Y.Habu, K.Wada, M.Miura, T.Tachibana, T.Honda, K.Tsunoda, H.Kitazawa, T.Kawabe, Y.Igawa, T.Hattori, K.Nezu, J.

(2017) Sci Rep 7: 1080-1080

  • DOI: https://doi.org/10.1038/s41598-017-01087-7
  • Primary Citation of Related Structures:  
    5B71

  • PubMed Abstract: 

    Dysregulation of the complement system is linked to the pathogenesis of a variety of hematological disorders. Eculizumab, an anti-complement C5 monoclonal antibody, is the current standard of care for paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). However, because of high levels of C5 in plasma, eculizumab has to be administered biweekly by intravenous infusion. By applying recycling technology through pH-dependent binding to C5, we generated a novel humanized antibody against C5, SKY59, which has long-lasting neutralization of C5. In cynomolgus monkeys, SKY59 suppressed C5 function and complement activity for a significantly longer duration compared to a conventional antibody. Furthermore, epitope mapping by X-ray crystal structure analysis showed that a histidine cluster located on C5 is crucial for the pH-dependent interaction with SKY59. This indicates that the recycling effect of SKY59 is driven by a novel mechanism of interaction with its antigen and is distinct from other known pH-dependent antibodies. Finally, SKY59 showed neutralizing effect on C5 variant p.Arg885His, while eculizumab does not inhibit complement activity in patients carrying this mutation. Collectively, these results suggest that SKY59 is a promising new anti-C5 agent for patients with PNH and other complement-mediated disorders.


  • Organizational Affiliation

    Chugai Pharmabody Research Pte. Ltd., 3 Biopolis Drive, #07-11 to 16, Synapse, 138623, Singapore.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
SKY59 Fab light chain
A, C
217Homo sapiensMutation(s): 0 
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
SKY59 Fab heavy chain
B, D
228Homo sapiensMutation(s): 0 
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Complement C5 beta chain
E, F
110Homo sapiensMutation(s): 0 
Gene Names: C5CPAMD4
UniProt & NIH Common Fund Data Resources
Find proteins for P01031 (Homo sapiens)
Explore P01031 
Go to UniProtKB:  P01031
PHAROS:  P01031
GTEx:  ENSG00000106804 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP01031
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.11 Å
  • R-Value Free: 0.285 
  • R-Value Work: 0.246 
  • R-Value Observed: 0.248 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 39.79α = 89.18
b = 55.1β = 86.24
c = 127.76γ = 78.2
Software Package:
Software NamePurpose
XDSdata processing
Aimlessdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-05-03
    Type: Initial release
  • Version 1.1: 2023-11-08
    Changes: Data collection, Database references, Refinement description