2FV5

Crystal structure of TACE in complex with IK682


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.218 
  • R-Value Observed: 0.220 

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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

IK682, a tight binding inhibitor of TACE.

Niu, X.Umland, S.Ingram, R.Beyer, B.M.Liu, Y.H.Sun, J.Lundell, D.Orth, P.

(2006) Arch Biochem Biophys 451: 43-50

  • DOI: https://doi.org/10.1016/j.abb.2006.03.034
  • Primary Citation of Related Structures:  
    2FV5

  • PubMed Abstract: 

    TNFalpha converting enzyme (TACE) is the major metalloproteinase for the processing of TNFalpha, a key inflammatory cytokine. IK682, a hydroxamate compound, was reported to be a potent and specific TACE inhibitor [J.J. Duan, L. Chen, Z.R. Wasserman, Z. Lu, R.Q. Liu, M.B. Covington, M. Qian, K.D. Hardman, R.L. Magolda, R.C. Newton, D.D. Christ, R.R. Wexler, C.P. Decicco, J. Med. Chem. 45 (2002) 4954-4957]. The binding kinetics of IK682 and the ectodomain of human TACE was examined. The k(on) of IK682 was determined as 1.1+/-0.3 x 10(8) M(-1) min(-1). No detectable dissociation of IK682 from TACE was observed following dialysis, dilution, and extensive washing over a maximum of 72 h. This was in contrast to the rapid dissociation of IK682 from ADAM10. LC/MS analysis of the TACE-IK682 complex after dissociation under denaturing conditions indicated that the tight binding is not due to covalent interaction. The X-ray crystal structure of TACE-IK682 complex revealed multiple binding points at the S1' and S3' sites and the movement of a loop (from Ala349 to Gly442) to accommodate the binding of the quinolinyl group of IK682 at the S3' pocket. The conformational changes of TACE may contribute significantly to the high affinity binding as a result of a more stable TACE-inhibitor complex.


  • Organizational Affiliation

    Department of Inflammation and Infection, Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. xioda.niu@spcorp.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ADAM 17
A, B
261Homo sapiensMutation(s): 3 
Gene Names: ADAM17CSVPTACE
EC: 3.4.24.86
UniProt & NIH Common Fund Data Resources
Find proteins for P78536 (Homo sapiens)
Explore P78536 
Go to UniProtKB:  P78536
PHAROS:  P78536
GTEx:  ENSG00000151694 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP78536
Sequence Annotations
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
541 Binding MOAD:  2FV5 Ki: 0.03 (nM) from 1 assay(s)
BindingDB:  2FV5 Ki: min: 0.06, max: 0.56 (nM) from 2 assay(s)
IC50: min: 0.56, max: 350 (nM) from 4 assay(s)
PDBBind:  2FV5 Kd: 2.00e-3 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.218 
  • R-Value Observed: 0.220 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.614α = 90
b = 75.696β = 90
c = 103.258γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2006-07-04
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2017-10-18
    Changes: Refinement description
  • Version 1.4: 2021-10-20
    Changes: Database references, Derived calculations
  • Version 1.5: 2023-08-30
    Changes: Data collection, Refinement description