1DIC

STRUCTURE OF 3,4-DICHLOROISOCOUMARIN-INHIBITED FACTOR D


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.182 
  • R-Value Observed: 0.182 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Structure of 3,4-dichloroisocoumarin-inhibited factor D.

Cole, L.B.Kilpatrick, J.M.Chu, N.Babu, Y.S.

(1998) Acta Crystallogr D Biol Crystallogr 54: 711-717

  • DOI: https://doi.org/10.1107/s0907444997010457
  • Primary Citation of Related Structures:  
    1DIC

  • PubMed Abstract: 

    Factor D (D) is a serine protease essential in the activation of the alternative complement pathway. Only a few of the common serine protease inhibitors inhibit D, binding covalently to the serine hydroxyl of the catalytic triad. 3,4-Dichloroisocoumarin (DCI) is a mechanism-based inhibitor which inhibits most serine proteases and many esterases, including D. The structure of the enzyme:inhibitor covalent adduct of D with DCI, DCI:D, to a resolution of 1.8 A is described, which represents the first structural analysis of D with a mechanism-based inhibitor. The side chain of the ring-opened DCI moiety of the protein adduct undergoes chemical modification in the buffered solution, resulting in the formation of an alpha-hydroxy acid moiety through the nucleophilic substitution of both Cl atoms. The inhibited enzyme is similar in overall structure to the native enzyme, as well as to a variety of isocoumarin-inhibited trypsin and porcine pancreatic elastase (PPE) structures, yet notable differences are observed in the active site and binding mode of these small-molecule inhibitors. One region of the active site (residues 189-195) is relatively conserved between factor D, trypsin, and elastase with respect to amino-acid sequence and to conformation. Another region (residues 214-220) reflects the amino-acid substitutions and conformational flexibility between these enzymes. The carbonyl O atom of the DCI moiety was found to be oriented away from the oxyanion hole, which greatly contributes to the stability of the DCI:D adduct. The comparisons of the active sites between native factor D, DCI-inhibited factor D, and various inhibited trypsin and elastase (PPE) molecules are providing the chemical bases directing our design of novel, small-molecule pharmaceutical agents capable of modulating the alternative complement pathway.


  • Organizational Affiliation

    BioCryst Pharmaceuticals, Inc., 2190 Parkway Lake Drive, Birmingham, AL 35244-2812, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
FACTOR D228Homo sapiensMutation(s): 0 
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
DIC
Query on DIC

Download Ideal Coordinates CCD File 
B [auth A]3,4-DICHLOROISOCOUMARIN
C9 H4 Cl2 O2
SUGXUUGGLDCZKB-UHFFFAOYSA-N
O
Query on O

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
OXYGEN ATOM
O
XLYOFNOQVPJJNP-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.182 
  • R-Value Observed: 0.182 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 56.3α = 90
b = 51.57β = 106.05
c = 39.84γ = 90
Software Package:
Software NamePurpose
XENGENdata collection
XENGENdata reduction
X-PLORmodel building
X-PLORrefinement
XENGENdata scaling
X-PLORphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 1999-07-22
    Type: Initial release
  • Version 1.1: 2008-03-24
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-08-09
    Changes: Database references, Derived calculations, Other, Refinement description