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PDBsum entry 1xuc

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protein ligands metals Protein-protein interface(s) links
Hydrolase PDB id
1xuc
Jmol
Contents
Protein chains
169 a.a. *
Ligands
PB3 ×2
Metals
_ZN ×4
_CA ×4
Waters ×445
* Residue conservation analysis
PDB id:
1xuc
Name: Hydrolase
Title: Matrix metalloproteinase-13 complexed with non-zinc binding inhibitor
Structure: Collagenase 3. Chain: a, b. Fragment: catalytic domain. Synonym: matrix metalloproteinase-13, mmp-13. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Tetramer (from PQS)
Resolution:
1.70Å     R-factor:   0.175     R-free:   0.200
Authors: C.K.Engel,K.U.Wendt
Key ref:
C.K.Engel et al. (2005). Structural basis for the highly selective inhibition of MMP-13. Chem Biol, 12, 181-189. PubMed id: 15734645 DOI: 10.1016/j.chembiol.2004.11.014
Date:
26-Oct-04     Release date:   26-Oct-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P45452  (MMP13_HUMAN) -  Collagenase 3
Seq:
Struc:
471 a.a.
169 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   2 terms 
  Biological process     collagen catabolic process   2 terms 
  Biochemical function     metallopeptidase activity     3 terms  

 

 
DOI no: 10.1016/j.chembiol.2004.11.014 Chem Biol 12:181-189 (2005)
PubMed id: 15734645  
 
 
Structural basis for the highly selective inhibition of MMP-13.
C.K.Engel, B.Pirard, S.Schimanski, R.Kirsch, J.Habermann, O.Klingler, V.Schlotte, K.U.Weithmann, K.U.Wendt.
 
  ABSTRACT  
 
Inhibitors for matrix metalloproteinases (MMPs) are under investigation for the treatment of cancer, arthritis, and cardiovascular disease. Here, we report a class of highly selective MMP-13 inhibitors (pyrimidine dicarboxamides) that exhibit no detectable activity against other MMPs. The high-resolution X-ray structures of three molecules of this series bound to MMP-13 reveal a novel binding mode characterized by the absence of interactions between the inhibitors and the catalytic zinc. The inhibitors bind in the S1' pocket and extend into an additional S1' side pocket, which is unique to MMP-13. We analyze the determinants for selectivity and describe the rational design of improved compounds with low nanomolar affinity.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. Binding Mode of Pyrimidine Dicarboxamides Exemplified by Inhibitor 1
Figure 3.
Figure 3. Protein/Inhibitor Interactions
 
  The above figures are reprinted by permission from Cell Press: Chem Biol (2005, 12, 181-189) copyright 2005.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21087458 E.Hadler-Olsen, B.Fadnes, I.Sylte, L.Uhlin-Hansen, and J.O.Winberg (2011).
Regulation of matrix metalloproteinase activity in health and disease.
  FEBS J, 278, 28-45.  
20481653 G.Dormán, S.Cseh, I.Hajdú, L.Barna, D.Kónya, K.Kupai, L.Kovács, and P.Ferdinandy (2010).
Matrix metalloproteinase inhibitors: a critical appraisal of design principles and proposed therapeutic utility.
  Drugs, 70, 949-964.  
19619515 A.C.Nicolescu, A.Holt, A.D.Kandasamy, P.Pacher, and R.Schulz (2009).
Inhibition of matrix metalloproteinase-2 by PARP inhibitors.
  Biochem Biophys Res Commun, 387, 646-650.  
19616423 C.J.Morrison, G.S.Butler, D.Rodríguez, and C.M.Overall (2009).
Matrix metalloproteinase proteomics: substrates, targets, and therapy.
  Curr Opin Cell Biol, 21, 645-653.  
19597572 C.Zhang, and S.K.Kim (2009).
Matrix metalloproteinase inhibitors (MMPIs) from marine natural products: the current situation and future prospects.
  Mar Drugs, 7, 71-84.  
19042129 N.Carrascal, and R.C.Rizzo (2009).
Calculation of binding free energies for non-zinc chelating pyrimidine dicarboxamide inhibitors with MMP-13.
  Bioorg Med Chem Lett, 19, 47-50.  
18775985 A.S.Dabert-Gay, B.Czarny, L.Devel, F.Beau, E.Lajeunesse, S.Bregant, R.Thai, A.Yiotakis, and V.Dive (2008).
Molecular Determinants of Matrix Metalloproteinase-12 Covalent Modification by a Photoaffinity Probe: INSIGHTS INTO ACTIVITY-BASED PROBE DEVELOPMENT AND CONFORMATIONAL VARIABILITY OF MATRIX METALLOPROTEINASES.
  J Biol Chem, 283, 31058-31067.  
18042679 L.T.Gooljarsingh, A.Lakdawala, F.Coppo, L.Luo, G.B.Fields, P.J.Tummino, and R.R.Gontarek (2008).
Characterization of an exosite binding inhibitor of matrix metalloproteinase 13.
  Protein Sci, 17, 66-71.  
18466418 N.Kaludercic, M.L.Lindsey, B.Tavazzi, G.Lazzarino, and N.Paolocci (2008).
Inhibiting metalloproteases with PD 166793 in heart failure: impact on cardiac remodeling and beyond.
  Cardiovasc Ther, 26, 24-37.  
  19183702 Y.Huang, and T.R.Pettus (2008).
A Cycloaddition Strategy for Use toward Berkelic Acid, an MMP Inhibitor and Potent Anticancer Agent Displaying a Unique Chroman Spiroketal Motif.
  Synlett, 9, 1353-1356.  
17623656 A.R.Johnson, A.G.Pavlovsky, D.F.Ortwine, F.Prior, C.F.Man, D.A.Bornemeier, C.A.Banotai, W.T.Mueller, P.McConnell, C.Yan, V.Baragi, C.Lesch, W.H.Roark, M.Wilson, K.Datta, R.Guzman, H.K.Han, and R.D.Dyer (2007).
Discovery and characterization of a novel inhibitor of matrix metalloprotease-13 that reduces cartilage damage in vivo without joint fibroplasia side effects.
  J Biol Chem, 282, 27781-27791.
PDB codes: 2ow9 2ozr
16710861 M.Matziari, V.Dive, and A.Yiotakis (2007).
Matrix metalloproteinase 11 (MMP-11; stromelysin-3) and synthetic inhibitors.
  Med Res Rev, 27, 528-552.  
16538215 C.M.Overall, and O.Kleifeld (2006).
Towards third generation matrix metalloproteinase inhibitors for cancer therapy.
  Br J Cancer, 94, 941-946.  
16680577 J.F.Fisher, and S.Mobashery (2006).
Recent advances in MMP inhibitor design.
  Cancer Metastasis Rev, 25, 115-136.  
16569256 J.P.Pelletier, J.Martel-Pelletier, and J.P.Raynauld (2006).
Most recent developments in strategies to reduce the progression of structural changes in osteoarthritis: today and tomorrow.
  Arthritis Res Ther, 8, 206.  
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 codes are shown on the right.