5TCA

Complement Factor D inhibited with JH3


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.15 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.225 
  • R-Value Observed: 0.227 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Buried Hydrogen Bond Interactions Contribute to the High Potency of Complement Factor D Inhibitors.

Yang, C.Y.Phillips, J.G.Stuckey, J.A.Bai, L.Sun, H.Delproposto, J.Brown, W.C.Chinnaswamy, K.

(2016) ACS Med Chem Lett 7: 1092-1096

  • DOI: https://doi.org/10.1021/acsmedchemlett.6b00299
  • Primary Citation of Related Structures:  
    5TCA, 5TCC

  • PubMed Abstract: 

    Aberrant activation of the complement system is associated with diseases, including paroxysmal nocturnal hemoglobinuria and age-related macular degeneration. Complement factor D is the rate-limiting enzyme for activating the alternative pathway in the complement system. Recent development led to a class of potent amide containing pyrrolidine derived factor D inhibitors. Here, we used biochemical enzymatic and biolayer interferometry assays to demonstrate that the amide group improves the inhibitor potency by more than 80-fold. Our crystal structures revealed buried hydrogen bond interactions are important. Molecular orbital analysis from quantum chemistry calculations dissects the chemical groups participating in these interactions. Free energy calculation supports the differential contributions of the amide group to the binding affinities of these inhibitors. Cell-based hemolysis assay confirmed these compounds inhibit factor D mediated complement activation via the alternative pathway. Our study highlights the important interactions contributing to the high potency of factor D inhibitors reported recently.


  • Organizational Affiliation

    Departments of Internal Medicine and Biological Chemistry and Life Sciences Institute, University of Michigan , Ann Arbor, Michigan 48109, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Complement factor D
A, B, C, D, E
A, B, C, D, E, F, G
228Homo 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
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
J55 BindingDB:  5TCA Kd: 19 (nM) from 1 assay(s)
IC50: min: 19, max: 205 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.15 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.225 
  • R-Value Observed: 0.227 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 99.361α = 90
b = 143.654β = 90
c = 347.592γ = 90
Software Package:
Software NamePurpose
HKL-2000data scaling
MOLREPphasing
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Cancer Institute (NIH/NCI)United StatesP30CA046592

Revision History  (Full details and data files)

  • Version 1.0: 2016-10-19
    Type: Initial release
  • Version 1.1: 2017-01-04
    Changes: Database references
  • Version 1.2: 2017-09-20
    Changes: Author supporting evidence
  • Version 1.3: 2019-12-04
    Changes: Author supporting evidence
  • Version 1.4: 2023-10-04
    Changes: Data collection, Database references, Refinement description