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Hydrolase/hydrolase inhibitor PDB id
1b3d
Jmol
Contents
Protein chains
169 a.a. *
Ligands
S27
Metals
_CA ×6
_ZN ×4
Waters ×120
* Residue conservation analysis
PDB id:
1b3d
Name: Hydrolase/hydrolase inhibitor
Title: Stromelysin-1
Structure: Stromelysin-1. Chain: a, b. Synonym: mmp-3. Engineered: yes. Other_details: stromelysin-1 complex with hydroxamate- phosphinamide inhibitor
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
2.30Å     R-factor:   0.256     R-free:   0.263
Authors: L.Chen,T.J.Rydel,C.M.Dunaway,S.Pikul,K.M.Dunham,F.Gu, B.L.Barnett
Key ref:
L.Chen et al. (1999). Crystal structure of the stromelysin catalytic domain at 2.0 A resolution: inhibitor-induced conformational changes. J Mol Biol, 293, 545-557. PubMed id: 10543949 DOI: 10.1006/jmbi.1999.3147
Date:
09-Dec-98     Release date:   10-Dec-99    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P08254  (MMP3_HUMAN) -  Stromelysin-1
Seq:
Struc: 		477 a.a.
169 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.4.24.17  - Stromelysin 1.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Preferential cleavage where P1', P2' and P3' are hydrophobic residues.
      Cofactor: Calcium; Zinc
 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: 10.1006/jmbi.1999.3147 J Mol Biol 293:545-557 (1999)
PubMed id: 10543949  
 
 
Crystal structure of the stromelysin catalytic domain at 2.0 A resolution: inhibitor-induced conformational changes.
L.Chen, T.J.Rydel, F.Gu, C.M.Dunaway, S.Pikul, K.M.Dunham, B.L.Barnett.
 
  ABSTRACT  
 
Matrix metalloproteinases are believed to play an important role in pathological conditions such as osteoarthritis, rheumatoid arthritis and tumor invasion. Stromelysin is a zinc-dependent proteinase and a member of the matrix metalloproteinase family. We have solved the crystal structure of an active uninhibited form of truncated stromelysin and a complex with a hydroxamate-based inhibitor. The catalytic domain of the enzyme of residues 83-255 is an active fragment. Two crystallographically independent molecules, A and B, associate as a dimer in the crystals. There are three alpha-helices and one twisted, five-strand beta-sheet in each molecule, as well as one catalytic Zn, one structural Zn and three structural Ca ions. The active site of stromelysin is located in a large, hydrophobic cleft. In particular, the S1' specificity site is a deep and highly hydrophobic cavity. The structure of a hydroxamate-phosphinamide-type inhibitor-bound stromelysin complex, formed by diffusion soaking, has been solved as part of our structure-based design strategy. The most important feature we observed is an inhibitor-induced conformational change in the S1' cavity which is triggered by Tyr223. In the uninhibited enzyme structure, Tyr223 completely covers the S1' cavity, while in the complex, the P1' group of the inhibitor displaces the Tyr223 in order to fit into the S1' cavity. Furthermore, the displacement of Tyr223 induces a major conformational change of the entire loop from residue 222 to residue 231. This finding provides direct evidence that Tyr223 plays the role of gatekeeper of the S1' cavity. Another important intermolecular interaction occurs at the active sit of molecule A, in which the C-terminal tail (residues 251-255) from molecule B inserts. The C-terminal tail interacts extensively with the active site of molecule A, and the last residue (Thr255) coordinated to the catalytic zinc as the fourth ligand, much like a product inhibitor would. The inhibitor-induced conformational change and the intermolecular C-terminal-zinc coordination are significant in understanding the structure-activity relationships of the enzyme.
 
  Selected figure(s)  
 
Figure 5.
Figure 5. The S1 binding pocket of RHTS with the inhibitor PGV-25727: cross-section view showing the cavity size. 		Figure 9.
Figure 9. Hydrophobicity comparison of the active sites: (a) MMP1; (b) MMP3 (green for hydrophobic and grey for hydrophilic).
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (1999, 293, 545-557) copyright 1999.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
17763953 H.P.Shin, J.I.Lee, J.H.Jung, S.V.Yim, H.J.Kim, J.M.Cha, J.B.Park, K.R.Joo, J.S.Hwang, and B.K.Jang (2008).
Matrix metalloproteinase (MMP)-3 polymorphism in patients with HBV related chronic liver disease.
  Dig Dis Sci, 53, 823-829.  
18554254 M.Fernández, L.Fernández, J.Caballero, J.I.Abreu, and G.Reyes (2008).
Proteochemometric modeling of the inhibition complexes of matrix metalloproteinases with N-hydroxy-2-[(phenylsulfonyl)amino]acetamide derivatives using topological autocorrelation interaction matrix and model ensemble averaging.
  Chem Biol Drug Des, 72, 65-78.  
17607744 A.Khandelwal, and S.Balaz (2007).
QM/MM linear response method distinguishes ligand affinities for closely related metalloproteins.
  Proteins, 69, 326-339.  
17163561 F.E.Jacobsen, J.A.Lewis, and S.M.Cohen (2007).
The Design of Inhibitors for Medicinally Relevant Metalloproteins.
  ChemMedChem, 2, 152-171.  
17710450 L.A.Alcaraz, L.Banci, I.Bertini, F.Cantini, A.Donaire, and L.Gonnelli (2007).
Matrix metalloproteinase-inhibitor interaction: the solution structure of the catalytic domain of human matrix metalloproteinase-3 with different inhibitors.
  J Biol Inorg Chem, 12, 1197-1206.
PDB codes: 2jnp 2jt5 2jt6
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
14718924 B.E.Turk, T.Y.Wong, R.Schwarzenbacher, E.T.Jarrell, S.H.Leppla, R.J.Collier, R.C.Liddington, and L.C.Cantley (2004).
The structural basis for substrate and inhibitor selectivity of the anthrax lethal factor.
  Nat Struct Mol Biol, 11, 60-66.
PDB codes: 1pwq 1pwu 1pwv 1pww
14732707 V.Lukacova, Y.Zhang, M.Mackov, P.Baricic, S.Raha, J.A.Calvo, and S.Balaz (2004).
Similarity of binding sites of human matrix metalloproteinases.
  J Biol Chem, 279, 14194-14200.  
11981330 K.Jaovisidha, and A.K.Rosenthal (2002).
Calcium crystals in osteoarthritis.
  Curr Opin Rheumatol, 14, 298-302.  
12077439 P.A.Elkins, Y.S.Ho, W.W.Smith, C.A.Janson, K.J.D'Alessio, M.S.McQueney, M.D.Cummings, and A.M.Romanic (2002).
Structure of the C-terminally truncated human ProMMP9, a gelatin-binding matrix metalloproteinase.
  Acta Crystallogr D Biol Crystallogr, 58, 1182-1192.
PDB code: 1l6j
11248710 V.Knäuper, M.L.Patterson, F.X.Gomis-Rüth, B.Smith, A.Lyons, A.J.Docherty, and G.Murphy (2001).
The role of exon 5 in fibroblast collagenase (MMP-1) substrate specificity and inhibitor selectivity.
  Eur J Biochem, 268, 1888-1896.  
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.