5FBI

COMPLEMENT FACTOR D IN COMPLEX WITH COMPOUND 3b


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.47 Å
  • R-Value Free: 0.196 
  • R-Value Work: 0.173 
  • R-Value Observed: 0.174 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Small-molecule factor D inhibitors targeting the alternative complement pathway.

Maibaum, J.Liao, S.M.Vulpetti, A.Ostermann, N.Randl, S.Rudisser, S.Lorthiois, E.Erbel, P.Kinzel, B.Kolb, F.A.Barbieri, S.Wagner, J.Durand, C.Fettis, K.Dussauge, S.Hughes, N.Delgado, O.Hommel, U.Gould, T.Mac Sweeney, A.Gerhartz, B.Cumin, F.Flohr, S.Schubart, A.Jaffee, B.Harrison, R.Risitano, A.M.Eder, J.Anderson, K.

(2016) Nat Chem Biol 12: 1105-1110

  • DOI: https://doi.org/10.1038/nchembio.2208
  • Primary Citation of Related Structures:  
    5FAH, 5FBE, 5FBI, 5FCK, 5FCR

  • PubMed Abstract: 

    Complement is a key component of the innate immune system, recognizing pathogens and promoting their elimination. Complement component 3 (C3) is the central component of the system. Activation of C3 can be initiated by three distinct routes-the classical, the lectin and the alternative pathways-with the alternative pathway also acting as an amplification loop for the other two pathways. The protease factor D (FD) is essential for this amplification process, which, when dysregulated, predisposes individuals to diverse disorders including age-related macular degeneration and paroxysmal nocturnal hemoglobinuria (PNH). Here we describe the identification of potent and selective small-molecule inhibitors of FD. These inhibitors efficiently block alternative pathway (AP) activation and prevent both C3 deposition onto, and lysis of, PNH erythrocytes. Their oral administration inhibited lipopolysaccharide-induced AP activation in FD-humanized mice. These data demonstrate the feasibility of inhibiting the AP with small-molecule antagonists and support the development of FD inhibitors for the treatment of complement-mediated diseases.


  • Organizational Affiliation

    Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, Basel, Switzerland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Complement factor D232Homo sapiensMutation(s): 0 
Gene Names: CFDDFPFD
EC: 3.4.21.46
UniProt & NIH Common Fund Data Resources
Find proteins for P00746 (Homo sapiens)
Explore P00746 
Go to UniProtKB:  P00746
PHAROS:  P00746
GTEx:  ENSG00000197766 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00746
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
5WD
Query on 5WD

Download Ideal Coordinates CCD File 
C [auth A]3-[(2-aminocarbonyl-1~{H}-indol-5-yl)oxymethyl]benzoic acid
C17 H14 N2 O4
JPBFPBAFCGZOAS-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
B [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
5WD BindingDB:  5FBI Kd: 1.60e+6 (nM) from 1 assay(s)
IC50: 2.90e+5 (nM) from 1 assay(s)
Binding MOAD:  5FBI Kd: 1.60e+6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.47 Å
  • R-Value Free: 0.196 
  • R-Value Work: 0.173 
  • R-Value Observed: 0.174 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 55.067α = 90
b = 50.655β = 105.35
c = 39.326γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
XSCALEdata scaling
BUSTERrefinement
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-10-26
    Type: Initial release
  • Version 1.1: 2016-11-02
    Changes: Database references
  • Version 1.2: 2016-11-23
    Changes: Database references
  • Version 1.3: 2024-01-10
    Changes: Data collection, Database references, Refinement description