PDBsum entry 1gvl

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protein links
Hydrolase PDB id
Protein chain
223 a.a. *
Waters ×158
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Human prokallikrein 6 (hk6)/ prozyme/ proprotease m/ proneurosin
Structure: Kallikrein 6. Chain: a. Synonym: human prokallikrein 6, protease m, neurosin, zyme. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: pichia pastoris. Expression_system_taxid: 4922.
1.8Å     R-factor:   0.185     R-free:   0.225
Authors: F.X.Gomis-Ruth,A.Bayes,G.Sotiropoulou,G.Pampalakis, T.Tsetsenis,V.Villegas,F.X.Aviles,M.Coll
Key ref:
F.X.Gomis-Rüth et al. (2002). The structure of human prokallikrein 6 reveals a novel activation mechanism for the kallikrein family. J Biol Chem, 277, 27273-27281. PubMed id: 12016211 DOI: 10.1074/jbc.M201534200
14-Feb-02     Release date:   16-May-02    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q92876  (KLK6_HUMAN) -  Kallikrein-6
244 a.a.
223 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   12 terms 
  Biological process     neuron death   13 terms 
  Biochemical function     catalytic activity     6 terms  


DOI no: 10.1074/jbc.M201534200 J Biol Chem 277:27273-27281 (2002)
PubMed id: 12016211  
The structure of human prokallikrein 6 reveals a novel activation mechanism for the kallikrein family.
F.X.Gomis-Rüth, A.Bayés, G.Sotiropoulou, G.Pampalakis, T.Tsetsenis, V.Villegas, F.X.Avilés, M.Coll.
Zyme/protease M/neurosin/human kallikrein 6 (hK6) is a member of the human kallikrein family of trypsin-like serine proteinases and was originally identified as being down-regulated in metastatic breast and ovarian tumors when compared with corresponding primary tumors. Recent evidence suggests that hK6 may serve as a circulating tumor marker in ovarian cancers. In addition, it was described in the brain of Parkinson's disease and Alzheimer's disease patients, where it is implicated in amyloid precursor protein processing. It is thus a biomarker for these diseases. To examine the mechanism of activation of hK6, we have solved the structure of its proform, the first of a human kallikrein family member. The proenzyme displays a fold that exhibits chimeric features between those of trypsinogen and other family members. It lacks the characteristic "kallikrein loop" and forms the six disulfide bridges of trypsin. Pro-hK6 displays a completely closed specificity pocket and a unique conformation of the regions involved in structural rearrangements upon proteolytic cleavage activation. This points to a novel activation mechanism, which could be extrapolated to other human kallikreins.
  Selected figure(s)  
Figure 2.
Fig. 2. Structure solution and pro-hK6 topology. a, stereo schematic diagram displaying the [A]-weighted 2mF[o] DF[c] electron density map obtained after ARP/wARP refinement, superimposed with the model used for initial phasing, contoured at 1 above average. b, same as a, with the final refined model superimposed. c, stereo ribbon plot of pro-hK6 shown in the traditional serine proteinase standard orientation (79) (i.e. looking into the active site cleft) with a bound substrate running from the left (nonprimed subsites prior to the scissile peptide bond; Ref. 64) to right (primed subsites). The regular secondary structure elements are displayed as arrows ( -strands) and ribbons ( -helices) and labeled ( [1]- [12] and [1]- [2]). The side chains of the residues of the catalytic triad (light gray) and the six disulfide bonds (dark gray; SS1-SS6) are also shown as stick models and labeled. The N and C termini and the positions of characteristic structural loops are also indicated, and poorly defined and undefined main-chain stretches (see "Experimental Procedures") are shown as dark gray coils.
Figure 4.
Fig. 4. Proposed activation of pro-hK6. a, superimposition of the C- traces of pro-hK6 (dark sticks) and neuropsin (light sticks) shown in standard orientation. b, close up view of the regions of pro-hK6 putatively involved in major structural rearrangements upon activation (dark sticks and labels) superimposed with the equivalent zones of neuropsin (light trace and labels), considered as a structural homologue of active hK6. c, scheme highlighting the proposed structural rearrangements observed on going from pro-hK6 (dark coil) to neuropsin (light coil).
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2002, 277, 27273-27281) copyright 2002.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21543845 A.Sukhwal, M.Bhattacharyya, and S.Vishveshwara (2011).
Network approach for capturing ligand-induced subtle global changes in protein structures.
  Acta Crystallogr D Biol Crystallogr, 67, 429-439.  
21072173 A.Pavlopoulou, G.Pampalakis, I.Michalopoulos, and G.Sotiropoulou (2010).
Evolutionary history of tissue kallikreins.
  PLoS One, 5, e13781.  
20302517 N.Beaufort, K.Plaza, D.Utzschneider, A.Schwarz, J.M.Burkhart, S.Creutzburg, M.Debela, M.Schmitt, C.Ries, and V.Magdolen (2010).
Interdependence of kallikrein-related peptidases in proteolytic networks.
  Biol Chem, 391, 581-587.  
20615447 P.Goettig, V.Magdolen, and H.Brandstetter (2010).
Natural and synthetic inhibitors of kallikrein-related peptidases (KLKs).
  Biochimie, 92, 1546-1567.  
19819870 G.Sotiropoulou, G.Pampalakis, and E.P.Diamandis (2009).
Functional roles of human kallikrein-related peptidases.
  J Biol Chem, 284, 32989-32994.  
20012271 N.Al-Hashimi, J.Y.Sire, and S.Delgado (2009).
Evolutionary analysis of mammalian enamelin, the largest enamel protein, supports a crucial role for the 32-kDa peptide and reveals selective adaptation in rodents and primates.
  J Mol Evol, 69, 635-656.  
19088065 U.Kuzmanov, N.Jiang, C.R.Smith, A.Soosaipillai, and E.P.Diamandis (2009).
Differential N-glycosylation of kallikrein 6 derived from ovarian cancer cells or the central nervous system.
  Mol Cell Proteomics, 8, 791-798.  
18697857 H.Yoon, S.I.Blaber, D.M.Evans, J.Trim, M.A.Juliano, I.A.Scarisbrick, and M.Blaber (2008).
Activation profiles of human kallikrein-related peptidases by proteases of the thrombostasis axis.
  Protein Sci, 17, 1998-2007.  
18844454 J.A.Clements (2008).
Reflections on the tissue kallikrein and kallikrein-related peptidase family - from mice to men - what have we learnt in the last two decades?
  Biol Chem, 389, 1447-1454.  
18627291 K.Oikonomopoulou, K.K.Hansen, A.Baruch, M.D.Hollenberg, and E.P.Diamandis (2008).
Immunofluorometric activity-based probe analysis of active KLK6 in biological fluids.
  Biol Chem, 389, 747-756.  
  17671364 I.S.Fernández, L.Ständker, W.G.Forssmann, G.Giménez-Gallego, and A.Romero (2007).
Crystallization and preliminary crystallographic studies of human kallikrein 7, a serine protease of the multigene kallikrein family.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 669-672.  
17417874 S.I.Blaber, H.Yoon, I.A.Scarisbrick, M.A.Juliano, and M.Blaber (2007).
The autolytic regulation of human kallikrein-related peptidase 6.
  Biochemistry, 46, 5209-5217.  
16800739 G.Pampalakis, and G.Sotiropoulou (2006).
Multiple mechanisms underlie the aberrant expression of the human kallikrein 6 gene in breast cancer.
  Biol Chem, 387, 773-782.  
16800734 N.Memari, L.Grass, T.Nakamura, I.Karakucuk, and E.P.Diamandis (2006).
Human tissue kallikrein 9: production of recombinant proteins and specific antibodies.
  Biol Chem, 387, 733-740.  
16800733 T.Kishi, S.M.Cloutier, C.Kündig, D.Deperthes, and E.P.Diamandis (2006).
Activation and enzymatic characterization of recombinant human kallikrein 8.
  Biol Chem, 387, 723-731.  
15651049 G.Laxmikanthan, S.I.Blaber, M.J.Bernett, I.A.Scarisbrick, M.A.Juliano, and M.Blaber (2005).
1.70 A X-ray structure of human apo kallikrein 1: structural changes upon peptide inhibitor/substrate binding.
  Proteins, 58, 802-814.
PDB code: 1spj
15255184 A.Bayés, T.Tsetsenis, S.Ventura, J.Vendrell, F.X.Aviles, and G.Sotiropoulou (2004).
Human kallikrein 6 activity is regulated via an autoproteolytic mechanism of activation/inactivation.
  Biol Chem, 385, 517-524.  
15516960 C.A.Borgoño, and E.P.Diamandis (2004).
The emerging roles of human tissue kallikreins in cancer.
  Nat Rev Cancer, 4, 876-890.  
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.