PDBsum entry 1s95

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protein ligands metals Protein-protein interface(s) links
Hydrolase PDB id
Protein chain
324 a.a. *
PO4 ×2
MPD ×2
_MN ×4
Waters ×463
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Structure of serine/threonine protein phosphatase 5
Structure: Serine/threonine protein phosphatase 5. Chain: a, b. Fragment: catalytic domain. Synonym: pp5, protein phosphatase t, pp-t, ppt. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ppp5c, ppp5. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.
Biol. unit: Dimer (from PQS)
1.60Å     R-factor:   0.171     R-free:   0.209
Authors: M.R.Swingle,R.E.Honkanen,E.M.Ciszak
Key ref:
M.R.Swingle et al. (2004). Structural basis for the catalytic activity of human serine/threonine protein phosphatase-5. J Biol Chem, 279, 33992-33999. PubMed id: 15155720 DOI: 10.1074/jbc.M402855200
03-Feb-04     Release date:   24-Aug-04    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P53041  (PPP5_HUMAN) -  Serine/threonine-protein phosphatase 5
499 a.a.
324 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Protein-serine/threonine phosphatase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: [a protein]-serine/threonine phosphate + H2O = [a protein]- serine/threonine + phosphate
[a protein]-serine/threonine phosphate
+ H(2)O
= [a protein]- serine/threonine
Bound ligand (Het Group name = PO4)
corresponds exactly
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   2 terms 
  Biological process     protein dephosphorylation   1 term 
  Biochemical function     hydrolase activity     2 terms  


    Key reference    
DOI no: 10.1074/jbc.M402855200 J Biol Chem 279:33992-33999 (2004)
PubMed id: 15155720  
Structural basis for the catalytic activity of human serine/threonine protein phosphatase-5.
M.R.Swingle, R.E.Honkanen, E.M.Ciszak.
Serine/threonine protein phosphatase-5 (PP5) affects many signaling networks that regulate cell growth and cellular responses to stress. Here we report the crystal structure of the PP5 catalytic domain (PP5c) at a resolution of 1.6 A. From this structure we propose a mechanism for PP5-mediated hydrolysis of phosphoprotein substrates, which requires the precise positioning of two metal ions within a conserved Asp271-M1:M2-W1-His427-His304-Asp274 catalytic motif (where M1 and M2 are metals and W1 is a water molecule). The structure of PP5c provides a structural basis for explaining the exceptional catalytic proficiency of protein phosphatases, which are among the most powerful known catalysts. Resolution of the entire C terminus revealed a novel subdomain, and the structure of the PP5c should also aid development of type-specific inhibitors.
  Selected figure(s)  
Figure 2.
FIG. 2. Catalytic site of PP5c. A, a stereoview of a 2F[o] - F[c] electron density map contoured at a 1.2 level overlaying the positions of amino acids and phosphate ion shown as stick models, and water molecules and metal ions shown as spheres. B, detailed representation of contacts within the active site. The hydrogen bonds are shown as yellow dotted lines, and coordination bonds to metal ions are shown as red solid lines. The green dotted line between the hydroxyl (W1) ion and phosphorus atom (P) represents a close contact (2.9 Å) suggestive of a near attack configuration in metal ion-mediated hydrolysis of phosphoprotein substrates.
Figure 3.
FIG. 3. Schematic representation of metal ion-mediated hydrolysis of substrate derived from the crystal structure of PP5c. The attacking hydroxide W1 is shown in blue, and the leaving group of the substrate is in green. The substrate, the planar PO[3] moiety of the transition state, and the phosphate product are all shown in red. Solid lines to the metal ions denote metal-ligand bonds, and solid or dashed wedges indicate metal-ligand bonds directed above or below the plane of the page, respectively. Wavy lines to the metal ions indicate strained contacts with poor coordination geometry. Dotted lines indicate hydrogen bonds, and the nearly dissociated axial bonds in the transition state are shown by half-dotted double lines.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 33992-33999) copyright 2004.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21360678 D.V.Skarra, M.Goudreault, H.Choi, M.Mullin, A.I.Nesvizhskii, A.C.Gingras, and R.E.Honkanen (2011).
Label-free quantitative proteomics and SAINT analysis enable interactome mapping for the human Ser/Thr protein phosphatase 5.
  Proteomics, 11, 1508-1516.  
20934451 D.W.Song, J.G.Lee, H.S.Youn, S.H.Eom, and d.o. .H.Kim (2011).
Ryanodine receptor assembly: A novel systems biology approach to 3D mapping.
  Prog Biophys Mol Biol, 105, 145-161.  
21288162 S.R.Pereira, V.T.Vasconcelos, and A.Antunes (2011).
The phosphoprotein phosphatase family of Ser/Thr phosphatases as principal targets of naturally occurring toxins.
  Crit Rev Toxicol, 41, 83.  
19299564 J.L.McConnell, and B.E.Wadzinski (2009).
Targeting protein serine/threonine phosphatases for drug development.
  Mol Pharmacol, 75, 1249-1261.  
19592665 M.R.Swingle, L.Amable, B.G.Lawhorn, S.B.Buck, C.P.Burke, P.Ratti, K.L.Fischer, D.L.Boger, and R.E.Honkanen (2009).
Structure-activity relationship studies of fostriecin, cytostatin, and key analogs, with PP1, PP2A, PP5, and( beta12-beta13)-chimeras (PP1/PP2A and PP5/PP2A), provide further insight into the inhibitory actions of fostriecin family inhibitors.
  J Pharmacol Exp Ther, 331, 45-53.  
19586900 Y.Zhang, D.Y.Leung, S.K.Nordeen, and E.Goleva (2009).
Estrogen inhibits glucocorticoid action via protein phosphatase 5 (PP5)-mediated glucocorticoid receptor dephosphorylation.
  J Biol Chem, 284, 24542-24552.  
18798625 C.McWhirter, E.A.Lund, E.A.Tanifum, G.Feng, Q.I.Sheikh, A.C.Hengge, and N.H.Williams (2008).
Mechanistic study of protein phosphatase-1 (PP1), a catalytically promiscuous enzyme.
  J Am Chem Soc, 130, 13673-13682.  
17951098 T.D.Hinds, and E.R.Sánchez (2008).
Protein phosphatase 5.
  Int J Biochem Cell Biol, 40, 2358-2362.  
18280813 T.Golden, I.V.Aragon, B.Rutland, J.A.Tucker, L.A.Shevde, R.S.Samant, G.Zhou, L.Amable, D.Skarra, and R.E.Honkanen (2008).
Elevated levels of Ser/Thr protein phosphatase 5 (PP5) in human breast cancer.
  Biochim Biophys Acta, 1782, 259-270.  
18253812 T.Golden, M.Swingle, and R.E.Honkanen (2008).
The role of serine/threonine protein phosphatase type 5 (PP5) in the regulation of stress-induced signaling networks and cancer.
  Cancer Metastasis Rev, 27, 169-178.  
17286284 C.Andreini, L.Banci, I.Bertini, S.Elmi, and A.Rosato (2007).
Non-heme iron through the three domains of life.
  Proteins, 67, 317-324.  
17939754 L.Ni, M.S.Swingle, A.C.Bourgeois, and R.E.Honkanen (2007).
High yield expression of serine/threonine protein phosphatase type 5, and a fluorescent assay suitable for use in the detection of catalytic inhibitors.
  Assay Drug Dev Technol, 5, 645-653.  
17177422 B.G.Lawhorn, S.B.Boga, S.E.Wolkenberg, D.A.Colby, C.M.Gauss, M.R.Swingle, L.Amable, R.E.Honkanen, and D.L.Boger (2006).
Total synthesis and evaluation of cytostatin, its C10-C11 diastereomers, and additional key analogues: impact on PP2A inhibition.
  J Am Chem Soc, 128, 16720-16732.  
16838328 D.Kumaran, J.B.Bonanno, S.K.Burley, and S.Swaminathan (2006).
Crystal structure of phosphatidylglycerophosphatase (PGPase), a putative membrane-bound lipid phosphatase, reveals a novel binuclear metal binding site and two "proton wires".
  Proteins, 64, 851-862.
PDB code: 1y9i
16407978 S.K.Wandinger, M.H.Suhre, H.Wegele, and J.Buchner (2006).
The phosphatase Ppt1 is a dedicated regulator of the molecular chaperone Hsp90.
  EMBO J, 25, 367-376.  
17055435 Y.Xing, Y.Xu, Y.Chen, P.D.Jeffrey, Y.Chao, Z.Lin, Z.Li, S.Strack, J.B.Stock, and Y.Shi (2006).
Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins.
  Cell, 127, 341-353.
PDB codes: 2ie3 2ie4
16954377 Z.Fu, K.A.Larson, R.K.Chitta, S.A.Parker, B.E.Turk, M.W.Lawrence, P.Kaldis, K.Galaktionov, S.M.Cohn, J.Shabanowitz, D.F.Hunt, and T.W.Sturgill (2006).
Identification of yin-yang regulators and a phosphorylation consensus for male germ cell-associated kinase (MAK)-related kinase.
  Mol Cell Biol, 26, 8639-8654.  
15577939 J.Yang, S.M.Roe, M.J.Cliff, M.A.Williams, J.E.Ladbury, P.T.Cohen, and D.Barford (2005).
Molecular basis for TPR domain-mediated regulation of protein phosphatase 5.
  EMBO J, 24, 1.
PDB code: 1wao
15780597 M.Gallego, and D.M.Virshup (2005).
Protein serine/threonine phosphatases: life, death, and sleeping.
  Curr Opin Cell Biol, 17, 197-202.  
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 code is shown on the right.