4WKI

Crystal structure of human ADAMTS-4 in complex with inhibitor 5-CHLORO-N-{[(4S)-4-(1-METHYL-1H-IMIDAZOL-2-YL)-2,5-DIOXOIMIDAZOLIDIN-4-YL]METHYL}-1-BENZOFURAN-2-CARBOXAMIDE (compound 11)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.200 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Identification of potent and selective hydantoin inhibitors of aggrecanase-1 and aggrecanase-2 that are efficacious in both chemical and surgical models of osteoarthritis.

Durham, T.B.Klimkowski, V.J.Rito, C.J.Marimuthu, J.Toth, J.L.Liu, C.Durbin, J.D.Stout, S.L.Adams, L.Swearingen, C.Lin, C.Chambers, M.G.Thirunavukkarasu, K.Wiley, M.R.

(2014) J Med Chem 57: 10476-10485

  • DOI: https://doi.org/10.1021/jm501522n
  • Primary Citation of Related Structures:  
    4WK7, 4WKE, 4WKI

  • PubMed Abstract: 

    A disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and ADAMTS-5 are zinc metalloproteases commonly referred to as aggrecanase-1 and aggrecanase-2, respectively. These enzymes are involved in the degradation of aggrecan, a key component of cartilage. Inhibitors of these enzymes could be potential osteoarthritis (OA) therapies. A series of hydantoin inhibitors of ADAMTS-4 and ADAMTS-5 were identified from a screening campaign and optimized through structure-based drug design to give hydantoin 13. Hydantoin 13 had excellent selectivity over other zinc metalloproteases such as TACE, MMP2, MMP3, MMP13, and MMP14. The compound also produced efficacy in both a chemically induced and surgical model of OA in rats.


  • Organizational Affiliation

    Eli Lilly and Company, Lilly Corporate Center , Indianapolis, Indiana 46285, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
A disintegrin and metalloproteinase with thrombospondin motifs 4235Homo sapiensMutation(s): 0 
Gene Names: ADAMTS4KIAA0688UNQ769/PRO1563
EC: 3.4.24.82
UniProt & NIH Common Fund Data Resources
Find proteins for O75173 (Homo sapiens)
Explore O75173 
Go to UniProtKB:  O75173
PHAROS:  O75173
GTEx:  ENSG00000158859 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO75173
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3PW
Query on 3PW

Download Ideal Coordinates CCD File 
G [auth A]5-chloro-N-{[(4S)-4-(1-methyl-1H-imidazol-2-yl)-2,5-dioxoimidazolidin-4-yl]methyl}-1-benzofuran-2-carboxamide
C17 H14 Cl N5 O4
NPWGFJCNOCYDSO-KRWDZBQOSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
B [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
F [auth A]1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A],
E [auth A]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
3PW BindingDB:  4WKI IC50: min: 3, max: 5 (nM) from 2 assay(s)
Binding MOAD:  4WKI IC50: 5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.200 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 40.037α = 90
b = 68.193β = 90
c = 74.013γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2014-12-10 
  • Deposition Author(s): Durbin, J.D.

Revision History  (Full details and data files)

  • Version 1.0: 2014-12-10
    Type: Initial release
  • Version 1.1: 2014-12-17
    Changes: Database references
  • Version 1.2: 2015-01-14
    Changes: Database references
  • Version 1.3: 2015-02-04
    Changes: Derived calculations
  • Version 1.4: 2023-12-27
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description, Source and taxonomy, Structure summary