4D9Q

Inhibiting Alternative Pathway Complement Activation by Targeting the Exosite on Factor D


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.28 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.191 

wwPDB Validation   3D Report Full Report


This is version 1.5 of the entry. See complete history


Literature

Inhibiting alternative pathway complement activation by targeting the factor d exosite.

Katschke, K.J.Wu, P.Ganesan, R.Kelley, R.F.Mathieu, M.A.Hass, P.E.Murray, J.Kirchhofer, D.Wiesmann, C.van Lookeren Campagne, M.

(2012) J Biol Chem 287: 12886-12892

  • DOI: https://doi.org/10.1074/jbc.M112.345082
  • Primary Citation of Related Structures:  
    4D9Q, 4D9R

  • PubMed Abstract: 

    By virtue of its amplifying property, the alternative complement pathway has been implicated in a number of inflammatory diseases and constitutes an attractive therapeutic target. An anti-factor D Fab fragment (AFD) was generated to inhibit the alternative complement pathway in advanced dry age-related macular degeneration. AFD potently prevented factor D (FD)-mediated proteolytic activation of its macromolecular substrate C3bB, but not proteolysis of a small synthetic substrate, indicating that AFD did not block access of the substrate to the catalytic site. The crystal structures of AFD in complex with human and cynomolgus FD (at 2.4 and 2.3 Å, respectively) revealed the molecular details of the inhibitory mechanism. The structures show that the AFD-binding site includes surface loops of FD that form part of the FD exosite. Thus, AFD inhibits FD proteolytic function by interfering with macromolecular substrate access rather than by inhibiting FD catalysis, providing the molecular basis of AFD-mediated inhibition of a rate-limiting step in the alternative complement pathway.


  • Organizational Affiliation

    Department of Immunology, Genentech Incorporated, South San Francisco, California 94080, USA.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Factor D
A, B
228Macaca mulattaMutation(s): 0 
UniProt
Find proteins for F6YBP7 (Macaca mulatta)
Explore F6YBP7 
Go to UniProtKB:  F6YBP7
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupF6YBP7
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Anti-Factor D, light chainC [auth D],
F [auth L]
213Homo sapiensMutation(s): 0 
UniProt
Find proteins for Q8TCD0 (Homo sapiens)
Explore Q8TCD0 
Go to UniProtKB:  Q8TCD0
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ8TCD0
Sequence Annotations
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Anti-Factor D, heavy chainD [auth E],
E [auth H]
217Homo sapiensMutation(s): 0 
Gene Names: IGHG1
UniProt & NIH Common Fund Data Resources
Find proteins for P01857 (Homo sapiens)
Explore P01857 
Go to UniProtKB:  P01857
PHAROS:  P01857
GTEx:  ENSG00000211896 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP01857
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
SO4
Query on SO4

Download Ideal Coordinates CCD File 
J [auth A],
K [auth A],
P [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

Download Ideal Coordinates CCD File 
G [auth A]
H [auth A]
L [auth B]
M [auth B]
N [auth B]
G [auth A],
H [auth A],
L [auth B],
M [auth B],
N [auth B],
Q [auth D],
R [auth D],
U [auth E],
V [auth E],
W [auth H]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
I [auth A]
O [auth B]
S [auth D]
T [auth D]
X [auth H]
I [auth A],
O [auth B],
S [auth D],
T [auth D],
X [auth H],
Y [auth L],
Z [auth L]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.28 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.191 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 182.33α = 90
b = 80.76β = 107.19
c = 142.63γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction
XSCALEdata scaling
BUSTERrefinement

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-02-22
    Type: Initial release
  • Version 1.1: 2012-03-14
    Changes: Database references
  • Version 1.2: 2012-05-02
    Changes: Database references
  • Version 1.3: 2014-04-02
    Changes: Structure summary
  • Version 1.4: 2017-08-02
    Changes: Refinement description, Source and taxonomy
  • Version 1.5: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description