PDBsum entry 1ros

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protein ligands metals Protein-protein interface(s) links
Hydrolase PDB id
Jmol PyMol
Protein chains
159 a.a. *
DEO ×2
_ZN ×4
_CA ×6
Waters ×276
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: 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
Structure: Macrophage metalloelastase. Chain: a, b. Fragment: residues 106-268. Synonym: hme, matrix metalloproteinase-12, mmp-12, macrophage elastase, me. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: mmp12, hme. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Trimer (from PQS)
2.00Å     R-factor:   0.199     R-free:   0.239
Authors: R.Morales,S.Perrier,J.M.Florent,J.Beltra,S.Dufour,I.De Mendez,P.Manceau,A.Tertre,F.Moreau,D.Compere,A.C.Dublanchet M.O'Gara
Key ref:
R.Morales et al. (2004). Crystal structures of novel non-peptidic, non-zinc chelating inhibitors bound to MMP-12. J Mol Biol, 341, 1063-1076. PubMed id: 15289103 DOI: 10.1016/j.jmb.2004.06.039
02-Dec-03     Release date:   07-Dec-04    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P39900  (MMP12_HUMAN) -  Macrophage metalloelastase
470 a.a.
159 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Macrophage elastase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Hydrolysis of soluble and insoluble elastin. Specific cleavages are also produced at 14-Ala-|-Leu-15 and 16-Tyr-|-Leu-17 in the B chain of insulin.
      Cofactor: Ca(2+); Zn(2+)
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular matrix   1 term 
  Biological process     wound healing   2 terms 
  Biochemical function     metallopeptidase activity     3 terms  


DOI no: 10.1016/j.jmb.2004.06.039 J Mol Biol 341:1063-1076 (2004)
PubMed id: 15289103  
Crystal structures of novel non-peptidic, non-zinc chelating inhibitors bound to MMP-12.
R.Morales, S.Perrier, J.M.Florent, J.Beltra, S.Dufour, I.De Mendez, P.Manceau, A.Tertre, F.Moreau, D.Compere, A.C.Dublanchet, M.O'Gara.
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.
  Selected figure(s)  
Figure 3.
Figure 3. Cross-section through the S10 pocket, with our inhibitors bound within, showing various degrees of interaction with the Zn cation.
Figure 8.
Figure 8. Residual Fo -- Fc electron density map (2s) located around the inhibitor, PD-0359601, after refinement using either R or S enantiomer.
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2004, 341, 1063-1076) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20139113 H.Williams, J.L.Johnson, C.L.Jackson, S.J.White, and S.J.George (2010).
MMP-7 mediates cleavage of N-cadherin and promotes smooth muscle cell apoptosis.
  Cardiovasc Res, 87, 137-146.  
18539597 R.Bhaskaran, M.O.Palmier, J.L.Lauer-Fields, G.B.Fields, and S.R.Van Doren (2008).
MMP-12 catalytic domain recognizes triple helical peptide models of collagen V with exosites and high activity.
  J Biol Chem, 283, 21779-21788.  
18214952 R.Minai, Y.Matsuo, H.Onuki, and H.Hirota (2008).
Method for comparing the structures of protein ligand-binding sites and application for predicting protein-drug interactions.
  Proteins, 72, 367-381.  
17163561 F.E.Jacobsen, J.A.Lewis, and S.M.Cohen (2007).
The Design of Inhibitors for Medicinally Relevant Metalloproteins.
  ChemMedChem, 2, 152-171.  
17997411 R.Bhaskaran, M.O.Palmier, N.A.Bagegni, X.Liang, and S.R.Van Doren (2007).
Solution structure of inhibitor-free human metalloelastase (MMP-12) indicates an internal conformational adjustment.
  J Mol Biol, 374, 1333-1344.
PDB code: 2poj
16498445 C.M.Overall, and O.Kleifeld (2006).
Tumour microenvironment - opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy.
  Nat Rev Cancer, 6, 227-239.  
16538215 C.M.Overall, and O.Kleifeld (2006).
Towards third generation matrix metalloproteinase inhibitors for cancer therapy.
  Br J Cancer, 94, 941-946.  
16481329 L.Devel, V.Rogakos, A.David, A.Makaritis, F.Beau, P.Cuniasse, A.Yiotakis, and V.Dive (2006).
Development of selective inhibitors and substrate of matrix metalloproteinase-12.
  J Biol Chem, 281, 11152-11160.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.