2USN

CRYSTAL STRUCTURE OF THE CATALYTIC DOMAIN OF HUMAN FIBROBLAST STROMELYSIN-1 INHIBITED WITH THIADIAZOLE INHIBITOR PNU-141803


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Work: 0.172 
  • R-Value Observed: 0.172 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Structural characterizations of nonpeptidic thiadiazole inhibitors of matrix metalloproteinases reveal the basis for stromelysin selectivity.

Finzel, B.C.Baldwin, E.T.Bryant Jr., G.L.Hess, G.F.Wilks, J.W.Trepod, C.M.Mott, J.E.Marshall, V.P.Petzold, G.L.Poorman, R.A.O'Sullivan, T.J.Schostarez, H.J.Mitchell, M.A.

(1998) Protein Sci 7: 2118-2126

  • DOI: https://doi.org/10.1002/pro.5560071008
  • Primary Citation of Related Structures:  
    1USN, 2USN

  • PubMed Abstract: 

    The binding of two 5-substituted-1,3,4-thiadiazole-2-thione inhibitors to the matrix metalloproteinase stromelysin (MMP-3) have been characterized by protein crystallography. Both inhibitors coordinate to the catalytic zinc cation via an exocyclic sulfur and lay in an unusual position across the unprimed (P1-P3) side of the proteinase active site. Nitrogen atoms in the thiadiazole moiety make specific hydrogen bond interactions with enzyme structural elements that are conserved across all enzymes in the matrix metalloproteinase class. Strong hydrophobic interactions between the inhibitors and the side chain of tyrosine-155 appear to be responsible for the very high selectivity of these inhibitors for stromelysin. In these enzyme/inhibitor complexes, the S1' enzyme subsite is unoccupied. A conformational rearrangement of the catalytic domain occurs that reveals an inherent flexibility of the substrate binding region leading to speculation about a possible mechanism for modulation of stromelysin activity and selectivity.


  • Organizational Affiliation

    Structural, Analytical & Medicinal Chemistry, Pharmacia and Upjohn, Kalamazoo, Michigan 49007, USA. Barry.C.Finzel@am.pnu.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
STROMELYSIN-1165Homo sapiensMutation(s): 0 
EC: 3.4.24.17
UniProt & NIH Common Fund Data Resources
Find proteins for P08254 (Homo sapiens)
Explore P08254 
Go to UniProtKB:  P08254
PHAROS:  P08254
GTEx:  ENSG00000149968 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP08254
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
IN8 Binding MOAD:  2USN Ki: 310 (nM) from 1 assay(s)
PDBBind:  2USN Ki: 310 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Work: 0.172 
  • R-Value Observed: 0.172 
  • Space Group: H 3 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 70.89α = 90
b = 70.89β = 90
c = 189.11γ = 120
Software Package:
Software NamePurpose
X-PLORmodel building
PROFFTrefinement
X-PLORrefinement
XENGENdata reduction
XENGENdata scaling
X-PLORphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 1998-12-23
    Type: Initial release
  • Version 1.1: 2008-03-25
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2018-03-07
    Changes: Data collection, Other
  • Version 1.4: 2023-08-09
    Changes: Database references, Derived calculations, Refinement description