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Hydrolase PDB id
1gkd
Jmol
Contents
Protein chains
159 a.a. *
Ligands
STN-BUM ×2
Metals
_ZN ×4
_CA ×8
Waters ×184
* Residue conservation analysis
PDB id:
1gkd
Name: Hydrolase
Title: Mmp9 active site mutant-inhibitor complex
Structure: 92 kda type iv collagenase. Chain: a, b. Fragment: catalytic domain residues 107-215,391-443. Synonym: mmp-9,92 kda gelatinase, gelatinase b, matrix metalloproteinase-9. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
2.1Å     R-factor:   0.212     R-free:   0.256
Authors: S.Rowsell,R.A.Pauptit
Key ref:
S.Rowsell et al. (2002). Crystal structure of human MMP9 in complex with a reverse hydroxamate inhibitor. J Mol Biol, 319, 173-181. PubMed id: 12051944 DOI: 10.1016/S0022-2836(02)00262-0
Date:
10-Aug-01     Release date:   16-May-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P14780  (MMP9_HUMAN) -  Matrix metalloproteinase-9
Seq:
Struc: 		 
Seq:
Struc: 		707 a.a.
159 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 46 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.3.4.24.35  - Gelatinase B.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Cleavage of gelatin types I and V and collagen types IV and V.
      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: 10.1016/S0022-2836(02)00262-0 J Mol Biol 319:173-181 (2002)
PubMed id: 12051944  
 
 
Crystal structure of human MMP9 in complex with a reverse hydroxamate inhibitor.
S.Rowsell, P.Hawtin, C.A.Minshull, H.Jepson, S.M.Brockbank, D.G.Barratt, A.M.Slater, W.L.McPheat, D.Waterson, A.M.Henney, R.A.Pauptit.
 
  ABSTRACT  
 
Matrix metalloproteinases (MMPs) and their inhibitors are important in connective tissue re-modelling in diseases of the cardiovascular system, such as atherosclerosis. Various members of the MMP family have been shown to be expressed in atherosclerotic lesions, but MMP9 is consistently seen in inflammatory atherosclerotic lesions. MMP9 over-expression is implicated in the vascular re-modelling events preceding plaque rupture (the most common cause of acute myocardial infarction). Reduced MMP9 activity, either by genetic manipulation or through pharmacological intervention, has an impact on ventricular re-modelling following infarction. MMP9 activity may therefore represent a key mechanism in the pathogenesis of heart failure. We have determined the crystal structure, at 2.3 A resolution, of the catalytic domain of human MMP9 bound to a peptidic reverse hydroxamate inhibitor as well as the complex of the same inhibitor bound to an active-site mutant (E402Q) at 2.1 A resolution. MMP9 adopts the typical MMP fold. The catalytic centre is composed of the active-site zinc ion, co-ordinated by three histidine residues (401, 405 and 411) and the essential glutamic acid residue (402). The main differences between the catalytic domains of various MMPs occur in the S1' subsite or selectivity pocket. The S1' specificity site in MMP9 is perhaps best described as a tunnel leading toward solvent, as in MMP2 and MMP13, as opposed to the smaller pocket found in fibroblast collagenase and matrilysin. The present structure enables us to aid the design of potent and specific inhibitors for this important cardiovascular disease target.
 
  Selected figure(s)  
 
Figure 4.
Figure 4. GRASP representation of wild-type MMP9 active site pocket with bound ligand. The enzyme surface is coloured by electrostatic potential, blue for positive and red for negative. Figure generated using the program GRASP.34 		Figure 6.
Figure 6. Stereo diagrams of the MMP9 active site. (a) Close-up of the wild-type MMP9 complex. A short (2.7 Å) hydrogen bond is formed between Glu402 and the inhibitor. (b) Close-up of the MMP9 (E402Q) mutant complex together with a portion of the (2F[o] -F[c]) electron density map. (c) Superposition of the mutant and wild-type active sites. The mutant structure is coloured as in (b); the wild-type structure is coloured dark grey. The structure is perturbed little on introduction of the mutation. The short hydrogen bond to the inhibitor seen in the wild-type complex is absent from the mutated structure (the corresponding atoms are 3.7 Å apart). This Figure was generated using BOBSCRIPT.31
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2002, 319, 173-181) copyright 2002.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20345904 A.Heinz, M.C.Jung, L.Duca, W.Sippl, S.Taddese, C.Ihling, A.Rusciani, G.Jahreis, A.S.Weiss, R.H.Neubert, and C.E.Schmelzer (2010).
Degradation of tropoelastin by matrix metalloproteinases--cleavage site specificities and release of matrikines.
  FEBS J, 277, 1939-1956.  
20305284 A.Prudova, U.auf dem Keller, G.S.Butler, and C.M.Overall (2010).
Multiplex N-terminome analysis of MMP-2 and MMP-9 substrate degradomes by iTRAQ-TAILS quantitative proteomics.
  Mol Cell Proteomics, 9, 894-911.  
20735854 B.Jiang, J.Chen, L.Xu, Z.Gao, Y.Deng, Y.Wang, F.Xu, X.Shen, and D.A.Guo (2010).
Salvianolic acid B functioned as a competitive inhibitor of matrix metalloproteinase-9 and efficiently prevented cardiac remodeling.
  BMC Pharmacol, 10, 10.  
20229282 D.Haller, P.Ekici, A.Friess, and H.Parlar (2010).
High enrichment of MMP-9 and carboxypeptidase A by tweezing adsorptive bubble separation (TABS).
  Appl Biochem Biotechnol, 162, 1547-1557.  
20871618 R.X.Yang, S.Y.Huang, F.F.Yan, X.T.Lu, Y.F.Xing, Y.Liu, Y.F.Liu, and Y.X.Zhao (2010).
Danshensu protects vascular endothelia in a rat model of hyperhomocysteinemia.
  Acta Pharmacol Sin, 31, 1395-1400.  
19065645 M.Jagodzinska, F.Huguenot, G.Candiani, and M.Zanda (2009).
Assessing the bioisosterism of the trifluoromethyl group with a protease probe.
  ChemMedChem, 4, 49-51.  
19707688 M.Rouffet, C.Denhez, E.Bourguet, F.Bohr, and D.Guillaume (2009).
In silico study of MMP inhibition.
  Org Biomol Chem, 7, 3817-3825.  
19243936 S.R.Ganta, S.Perumal, S.R.Pagadala, O.Samuelsen, J.Spencer, R.F.Pratt, and J.D.Buynak (2009).
Approaches to the simultaneous inactivation of metallo- and serine-beta-lactamases.
  Bioorg Med Chem Lett, 19, 1618-1622.  
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.  
18827560 M.H.Chen, S.X.Cui, Y.N.Cheng, L.R.Sun, Q.B.Li, W.F.Xu, S.G.Ward, W.Tang, and X.J.Qu (2008).
Galloyl cyclic-imide derivative CH1104I inhibits tumor invasion through suppressing matrix metalloproteinase activity.
  Anticancer Drugs, 19, 957-965.  
18452312 S.M.McCarthy, P.F.Bove, D.E.Matthews, T.Akaike, and A.van der Vliet (2008).
Nitric oxide regulation of MMP-9 activation and its relationship to modifications of the cysteine switch.
  Biochemistry, 47, 5832-5840.  
17660250 A.B.Hamze, S.Wei, H.Bahudhanapati, S.Kota, K.R.Acharya, and K.Brew (2007).
Constraining specificity in the N-domain of tissue inhibitor of metalloproteinases-1; gelatinase-selective inhibitors.
  Protein Sci, 16, 1905-1913.  
17333483 A.Khandelwal, and S.Balaz (2007).
Improved estimation of ligand-macromolecule binding affinities by linear response approach using a combination of multi-mode MD simulation and QM/MM methods.
  J Comput Aided Mol Des, 21, 131-137.  
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
17090320 L.R.Pal, and C.Guda (2006).
Tracing the origin of functional and conserved domains in the human proteome: implications for protein evolution at the modular level.
  BMC Evol Biol, 6, 91.  
17015178 P.Pei, M.P.Horan, R.Hille, C.F.Hemann, S.P.Schwendeman, and S.R.Mallery (2006).
Reduced nonprotein thiols inhibit activation and function of MMP-9: implications for chemoprevention.
  Free Radic Biol Med, 41, 1315-1324.  
  17357475 Y.Zhao, W.Feng, Y.Yang, L.Ling, and R.Chen (2006).
Comparison of properties of tumor necrosis factor-alpha converting enzyme (TACE) and some matrix metalloproteases (MMPs) in catalytic domains.
  J Huazhong Univ Sci Technolog Med Sci, 26, 637-639.  
16107143 A.Khandelwal, V.Lukacova, D.Comez, D.M.Kroll, S.Raha, and S.Balaz (2005).
A combination of docking, QM/MM methods, and MD simulation for binding affinity estimation of metalloprotein ligands.
  J Med Chem, 48, 5437-5447.  
15900322 A.L.Banerjee, S.Tobwala, M.K.Haldar, M.Swanson, B.C.Roy, S.Mallik, and D.K.Srivastava (2005).
Inhibition of matrix metalloproteinase-9 by "multi-prong" surface binding groups.
  Chem Commun (Camb), 0, 2549-2551.  
15849365 H.Yi, J.Gruszczynska-Biegala, D.Wood, Z.Zhao, and A.Zolkiewska (2005).
Cooperation of the metalloprotease, disintegrin, and cysteine-rich domains of ADAM12 during inhibition of myogenic differentiation.
  J Biol Chem, 280, 23475-23483.  
15907591 M.Björklund, and E.Koivunen (2005).
Gelatinase-mediated migration and invasion of cancer cells.
  Biochim Biophys Acta, 1755, 37-69.  
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
15601584 I.Svab, D.Alexandru, G.Vitos, and M.L.Flonta (2004).
Binding affinities for sulfonamide inhibitors with matrix metalloproteinase-2 using a linear response method.
  J Cell Mol Med, 8, 551-562.  
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.  
14532275 H.I.Park, Y.Jin, D.R.Hurst, C.A.Monroe, S.Lee, M.A.Schwartz, and Q.X.Sang (2003).
The intermediate S1' pocket of the endometase/matrilysin-2 active site revealed by enzyme inhibition kinetic studies, protein sequence analyses, and homology modeling.
  J Biol Chem, 278, 51646-51653.  
12621040 S.Steinbacher, J.Kaiser, W.Eisenreich, R.Huber, A.Bacher, and F.Rohdich (2003).
Structural basis of fosmidomycin action revealed by the complex with 2-C-methyl-D-erythritol 4-phosphate synthase (IspC). Implications for the catalytic mechanism and anti-malaria drug development.
  J Biol Chem, 278, 18401-18407.
PDB codes: 1onn 1ono 1onp
12887053 W.Bode, and K.Maskos (2003).
Structural basis of the matrix metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases.
  Biol Chem, 384, 863-872.  
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.