PDBsum entry 1hy7

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protein ligands metals Protein-protein interface(s) links
Hydrolase PDB id
Protein chains
162 a.a. *
171 a.a. *
_CA ×6
_ZN ×4
Waters ×336
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: A carboxylic acid based inhibitor in complex with mmp3
Structure: Stromelysin-1. Chain: a, b. Fragment: catalytic domain, residues 100-272. Synonym: mmp-3. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Cell: fibroblast. Gene: mmp3. Expressed in: escherichia coli. Expression_system_taxid: 562
1.50Å     R-factor:   0.190     R-free:   0.220
Authors: M.G.Natchus,R.G.Bookland,M.J.Laufersweiler,S.Pikul,N.G.Almst M.J.Janusz,L.C.Hsieh,F.Gu,M.E.Pokross,V.S.Patel,S.M.Garver, T.M.Branch,S.L.King,T.R.Baker,D.J.Foltz,G.E.Mieling
Key ref: M.G.Natchus et al. (2001). Development of new carboxylic acid-based MMP inhibitors derived from functionalized propargylglycines. J Med Chem, 44, 1060-1071. PubMed id: 11297453 DOI: 10.1021/jm000477l
18-Jan-01     Release date:   18-Jan-02    
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Protein chain
Pfam   ArchSchema ?
P08254  (MMP3_HUMAN) -  Stromelysin-1
477 a.a.
162 a.a.
Protein chain
Pfam   ArchSchema ?
P08254  (MMP3_HUMAN) -  Stromelysin-1
477 a.a.
171 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains A, B: E.C.  - Stromelysin 1.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Preferential cleavage where P1', P2' and P3' are hydrophobic residues.
      Cofactor: Ca(2+); Zn(2+)
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular matrix   1 term 
  Biological process     proteolysis   1 term 
  Biochemical function     metallopeptidase activity     3 terms  


DOI no: 10.1021/jm000477l J Med Chem 44:1060-1071 (2001)
PubMed id: 11297453  
Development of new carboxylic acid-based MMP inhibitors derived from functionalized propargylglycines.
M.G.Natchus, R.G.Bookland, M.J.Laufersweiler, S.Pikul, N.G.Almstead, B.De, M.J.Janusz, L.C.Hsieh, F.Gu, M.E.Pokross, V.S.Patel, S.M.Garver, S.X.Peng, T.M.Branch, S.L.King, T.R.Baker, D.J.Foltz, G.E.Mieling.
A series of carboxylic acids were prepared from a propargylglycine scaffold and tested for efficacy as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for four enzymes within the MMP family. The inhibitors were typically potent against collagenase-3 (MMP-13) and gelatinase A (MMP-2), while they spared collagenase-1 (MMP-1) and only moderately inhibited stromelysin (MMP-3). Compound 40 represents a typical inhibition profile of a compound with reasonable potency. Introduction of polar groups was required in order to generate inhibitors with acceptable water solubility, and this often resulted in a loss of potency as in compound 63. High serum protein binding proved to be a difficult hurdle with many compounds such as 48 showing >99% binding. Some compounds such as 64 displayed approximately 90% binding, but no reliable method was discovered for designing molecules with low protein binding. Finally, selected data regarding the pharmacokinetic behavior of these compounds is presented.

Literature references that cite this PDB file's key reference

  PubMed id Reference
19565489 V.M.Baragi, G.Becher, A.M.Bendele, R.Biesinger, H.Bluhm, J.Boer, H.Deng, R.Dodd, M.Essers, T.Feuerstein, B.M.Gallagher, C.Gege, M.Hochgürtel, M.Hofmann, A.Jaworski, L.Jin, A.Kiely, B.Korniski, H.Kroth, D.Nix, B.Nolte, D.Piecha, T.S.Powers, F.Richter, M.Schneider, C.Steeneck, I.Sucholeiki, A.Taveras, A.Timmermann, J.Van Veldhuizen, J.Weik, X.Wu, and B.Xia (2009).
A new class of potent matrix metalloproteinase 13 inhibitors for potential treatment of osteoarthritis: Evidence of histologic and clinical efficacy without musculoskeletal toxicity in rat models.
  Arthritis Rheum, 60, 2008-2018.  
16441234 M.Xue, N.T.Le, and C.J.Jackson (2006).
Targeting matrix metalloproteases to improve cutaneous wound healing.
  Expert Opin Ther Targets, 10, 143-155.  
16983671 S.Y.Huang, and X.Zou (2006).
An iterative knowledge-based scoring function to predict protein-ligand interactions: II. Validation of the scoring function.
  J Comput Chem, 27, 1876-1882.  
16172678 J.Kaiser, S.S.Kinderman, B.C.van Esseveldt, F.L.van Delft, H.E.Schoemaker, R.H.Blaauw, and F.P.Rutjes (2005).
Synthetic applications of aliphatic unsaturated alpha-H-alpha-amino acids.
  Org Biomol Chem, 3, 3435-3467.  
16216515 Y.Hu, J.S.Xiang, M.J.DiGrandi, X.Du, M.Ipek, L.M.Laakso, J.Li, W.Li, T.S.Rush, J.Schmid, J.S.Skotnicki, S.Tam, J.R.Thomason, Q.Wang, and J.I.Levin (2005).
Potent, selective, and orally bioavailable matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis.
  Bioorg Med Chem, 13, 6629-6644.  
12066962 M.A.Rudek, J.Venitz, and W.D.Figg (2002).
Matrix metalloproteinase inhibitors: do they have a place in anticancer therapy?
  Pharmacotherapy, 22, 705-720.  
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