1ROS

Crystal structure of MMP-12 complexed to 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl-4-(4-ethoxy[1,1-biphenyl]-4-yl)-4-oxobutanoic acid


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.239 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.199 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Crystal structures of novel non-peptidic, non-zinc chelating inhibitors bound to MMP-12.

Morales, R.Perrier, S.Florent, J.M.Beltra, J.Dufour, S.De Mendez, I.Manceau, P.Tertre, A.Moreau, F.Compere, D.Dublanchet, A.C.O'Gara, M.

(2004) J Mol Biol 341: 1063-1076

  • DOI: https://doi.org/10.1016/j.jmb.2004.06.039
  • Primary Citation of Related Structures:  
    1ROS, 1UTT, 1UTZ

  • PubMed Abstract: 

    Human macrophage elastase (MMP-12) plays an important role in inflammatory processes and has been implicated in diseases such as emphysema and chronic obstructive pulmonary disease (COPD). It is therefore an attractive target for therapeutic agents. As part of a structure-based drug design programme to find new inhibitors of MMP-12, the crystal structures of the MMP-12 catalytic domain (residues 106-268) complexed to three different non-peptidic small molecule inhibitors have been determined. The structures reveal that all three ligands bind in the S1' pocket but show varying degrees of interaction with the Zn atom. The structures of the complexes with inhibitors CP-271485 and PF-00356231 reveal that their central morpholinone and thiophene rings, respectively, sit over the Zn atom at a distance of approximately 5A, locating the inhibitors halfway down the S1' pocket. In both of these structures, an acetohydroxamate anion, an artefact of the crystallisation solution, chelates the zinc atom. By contrast, the acetohydroxamate anion is displaced by the ligand in the structure of MMP-12 complexed to PD-0359601 (Bayer), a potent zinc chelating N-substituted biaryl butyric acid, used as a reference compound for crystallisation. Although a racemate was used for the crystallisation, the S enantiomer only is bound in the crystal. Important hydrophobic interactions between the inhibitors and residues from the S1' pocket are observed in all of the structures. The relative selectivity displayed by these ligands for MMP-12 over other MMP family members is discussed.


  • Organizational Affiliation

    Pfizer Global Research and Development, Fresnes Laboratories, 94265 Fresnes Cedex, France [corrected]


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Macrophage metalloelastase
A, B
163Homo sapiensMutation(s): 0 
Gene Names: MMP12HME
EC: 3.4.24.65
UniProt & NIH Common Fund Data Resources
Find proteins for P39900 (Homo sapiens)
Explore P39900 
Go to UniProtKB:  P39900
PHAROS:  P39900
GTEx:  ENSG00000262406 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP39900
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
DEO
Query on DEO

Download Ideal Coordinates CCD File 
H [auth A],
N [auth B]
2-[2-(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)ETHYL]-4-(4'-ETHOXY-1,1'-BIPHENYL-4-YL)-4-OXOBUTANOIC ACID
C28 H25 N O6
AQYSXARQCHHHLK-NRFANRHFSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A],
I [auth B],
J [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
E [auth A]
F [auth A]
G [auth A]
K [auth B]
L [auth B]
E [auth A],
F [auth A],
G [auth A],
K [auth B],
L [auth B],
M [auth B]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
DEO Binding MOAD:  1ROS IC50: 1.7 (nM) from 1 assay(s)
PDBBind:  1ROS IC50: 1.7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.239 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.199 
  • Space Group: H 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 123.2α = 90
b = 123.2β = 90
c = 59.5γ = 120
Software Package:
Software NamePurpose
SCALEPACKdata scaling
AMoREphasing
CNSrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2004-12-07
    Type: Initial release
  • Version 1.1: 2008-04-29
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2017-10-11
    Changes: Refinement description
  • Version 1.4: 2023-08-23
    Changes: Data collection, Database references, Derived calculations, Refinement description