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PDBsum entry 2rjp
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protein ligands metals Protein-protein interface(s) links
Hydrolase PDB id
2rjp

 

 

 

 

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Contents
Protein chain
291 a.a. *
Ligands
886 ×4
Metals
_ZN ×4
_CA ×12
Waters ×120
* Residue conservation analysis
PDB id:
2rjp
Name: Hydrolase
Title: Crystal structure of adamts4 with inhibitor bound
Structure: Adamts-4. Chain: a, b, c, d. Fragment: residues 213-520. Synonym: a disintegrin and metalloproteinase with thrombospondin motifs 4, adam-ts 4, adam-ts4, aggrecanase-1, admp-1. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: adamts4, kiaa0688. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell_line: ovary (cho) cells
Resolution:
2.80Å     R-factor:   0.209     R-free:   0.267
Authors: L.Mosyak,M.Stahl,W.Somers
Key ref:
L.Mosyak et al. (2008). Crystal structures of the two major aggrecan degrading enzymes, ADAMTS4 and ADAMTS5. Protein Sci, 17, 16-21. PubMed id: 18042673 DOI: 10.1110/ps.073287008
Date:
15-Oct-07     Release date:   11-Dec-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
O75173  (ATS4_HUMAN) -  A disintegrin and metalloproteinase with thrombospondin motifs 4 from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		837 a.a.
291 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.3.4.24.82  - Adamts-4 endopeptidase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Cofactor: Zn(2+)

 

 
DOI no: 10.1110/ps.073287008 Protein Sci 17:16-21 (2008)
PubMed id: 18042673  
 
 
Crystal structures of the two major aggrecan degrading enzymes, ADAMTS4 and ADAMTS5.
L.Mosyak, K.Georgiadis, T.Shane, K.Svenson, T.Hebert, T.McDonagh, S.Mackie, S.Olland, L.Lin, X.Zhong, R.Kriz, E.L.Reifenberg, L.A.Collins-Racie, C.Corcoran, B.Freeman, R.Zollner, T.Marvell, M.Vera, P.E.Sum, E.R.Lavallie, M.Stahl, W.Somers.
 
  ABSTRACT  
 
Aggrecanases are now believed to be the principal proteinases responsible for aggrecan degradation in osteoarthritis. Given their potential as a drug target, we solved crystal structures of the two most active human aggrecanase isoforms, ADAMTS4 and ADAMTS5, each in complex with bound inhibitor and one wherein the enzyme is in apo form. These structures show that the unliganded and inhibitor-bound enzymes exhibit two essentially different catalytic-site configurations: an autoinhibited, nonbinding, closed form and an open, binding form. On this basis, we propose that mature aggrecanases exist as an ensemble of at least two isomers, only one of which is proteolytically active.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. Molecular surfaces of the active sites with inhibitor bound and detailed view of the interactions involved. (A) Stereo surface
 
  The above figure is reprinted by permission from the Protein Society: Protein Sci (2008, 17, 16-21) copyright 2008.  
  Figure was selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21370305 H.S.Shieh, A.G.Tomasselli, K.J.Mathis, M.E.Schnute, S.S.Woodard, N.Caspers, J.M.Williams, J.R.Kiefer, G.Munie, A.Wittwer, A.M.Malfait, and M.D.Tortorella (2011).
Structure analysis reveals the flexibility of the ADAMTS-5 active site.
  Protein Sci, 20, 735-744.
PDB codes: 3ljt 3ljz
21385852 M.Zhou, X.Dong, C.Baldauf, H.Chen, Y.Zhou, T.A.Springer, X.Luo, C.Zhong, F.Gräter, and J.Ding (2011).
A novel calcium-binding site of von Willebrand factor A2 domain regulates its cleavage by ADAMTS13.
  Blood, 117, 4623-4631.
PDB codes: 3ppv 3ppw 3ppx 3ppy
20379990 A.Cappelli, C.Nannicini, S.Valenti, G.Giuliani, M.Anzini, L.Mennuni, A.Giordani, G.Caselli, L.P.Stasi, F.Makovec, G.Giorgi, and S.Vomero (2010).
Design, synthesis, and preliminary biological evaluation of pyrrolo[3,4-c]quinolin-1-one and oxoisoindoline derivatives as aggrecanase inhibitors.
  ChemMedChem, 5, 739-748.  
20645923 N.H.Lim, M.Kashiwagi, R.Visse, J.Jones, J.J.Enghild, K.Brew, and H.Nagase (2010).
Reactive-site mutants of N-TIMP-3 that selectively inhibit ADAMTS-4 and ADAMTS-5: biological and structural implications.
  Biochem J, 431, 113-122.  
20647566 R.de Groot, D.A.Lane, and J.T.Crawley (2010).
The ADAMTS13 metalloprotease domain: roles of subsites in enzyme activity and specificity.
  Blood, 116, 3064-3072.  
19786614 H.B.Feys, I.Pareyn, R.Vancraenenbroeck, M.De Maeyer, H.Deckmyn, C.Van Geet, and K.Vanhoorelbeke (2009).
Mutation of the H-bond acceptor S119 in the ADAMTS13 metalloprotease domain reduces secretion and substrate turnover in a patient with congenital thrombotic thrombocytopenic purpura.
  Blood, 114, 4749-4752.  
19101611 H.E.Miwa, T.A.Gerken, T.D.Huynh, L.R.Duesler, M.Cotter, and T.M.Hering (2009).
Conserved sequence in the aggrecan interglobular domain modulates cleavage by ADAMTS-4 and ADAMTS-5.
  Biochim Biophys Acta, 1790, 161-172.  
19692335 H.Liu, A.H.Shim, and X.He (2009).
Structural characterization of the ectodomain of a disintegrin and metalloproteinase-22 (ADAM22), a neural adhesion receptor instead of metalloproteinase: insights on ADAM function.
  J Biol Chem, 284, 29077-29086.  
19643179 L.Troeberg, K.Fushimi, S.D.Scilabra, H.Nakamura, V.Dive, I.B.Thøgersen, J.J.Enghild, and H.Nagase (2009).
The C-terminal domains of ADAMTS-4 and ADAMTS-5 promote association with N-TIMP-3.
  Matrix Biol, 28, 463-469.  
19880749 M.Akiyama, S.Takeda, K.Kokame, J.Takagi, and T.Miyata (2009).
Crystal structures of the noncatalytic domains of ADAMTS13 reveal multiple discontinuous exosites for von Willebrand factor.
  Proc Natl Acad Sci U S A, 106, 19274-19279.
PDB codes: 3ghm 3ghn
  19574655 M.Akiyama, S.Takeda, K.Kokame, J.Takagi, and T.Miyata (2009).
Production, crystallization and preliminary crystallographic analysis of an exosite-containing fragment of human von Willebrand factor-cleaving proteinase ADAMTS13.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 65, 739-742.  
19047683 M.D.Gardner, C.K.Chion, R.de Groot, A.Shah, J.T.Crawley, and D.A.Lane (2009).
A functional calcium-binding site in the metalloprotease domain of ADAMTS13.
  Blood, 113, 1149-1157.  
18706512 S.Takeda (2009).
Three-dimensional domain architecture of the ADAM family proteinases.
  Semin Cell Dev Biol, 20, 146-152.  
18492952 W.Gao, P.J.Anderson, and J.E.Sadler (2008).
Extensive contacts between ADAMTS13 exosites and von Willebrand factor domain A2 contribute to substrate specificity.
  Blood, 112, 1713-1719.  
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.

 

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