PDBsum entry 1o86

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Hydrolase/hydrolase inhibitor PDB id
Protein chain
575 a.a. *
_CL ×2
Waters ×570
* Residue conservation analysis
PDB id:
Name: Hydrolase/hydrolase inhibitor
Title: Crystal structure of human angiotensin converting enzyme in with lisinopril.
Structure: Angiotensin converting enzyme. Chain: a. Fragment: residues 68-656. Synonym: ace-t, dipeptidyl carboxypeptidase i, kininase ii. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Organ: testis. Expressed in: cricetulus griseus. Expression_system_taxid: 10029
2.00Å     R-factor:   0.180     R-free:   0.220
Authors: R.Natesh,S.L.U.Schwager,E.D.Sturrock,K.R.Acharya
Key ref:
R.Natesh et al. (2003). Crystal structure of the human angiotensin-converting enzyme-lisinopril complex. Nature, 421, 551-554. PubMed id: 12540854 DOI: 10.1038/nature01370
25-Nov-02     Release date:   07-Feb-03    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P12821  (ACE_HUMAN) -  Angiotensin-converting enzyme
1306 a.a.
575 a.a.
Key:    PfamA domain  Secondary structure

 Enzyme reactions 
   Enzyme class: E.C.  - Peptidyl-dipeptidase A.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Release of a C-terminal dipeptide, oligopeptide-|-Xaa-Xbb, when Xaa is not Pro, and Xbb is neither Asp nor Glu. Converts angiotensin I to angiotensin II.
      Cofactor: Zinc
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   1 term 
  Biological process     proteolysis   1 term 
  Biochemical function     metallopeptidase activity     2 terms  


DOI no: 10.1038/nature01370 Nature 421:551-554 (2003)
PubMed id: 12540854  
Crystal structure of the human angiotensin-converting enzyme-lisinopril complex.
R.Natesh, S.L.Schwager, E.D.Sturrock, K.R.Acharya.
Angiotensin-converting enzyme (ACE) has a critical role in cardiovascular function by cleaving the carboxy terminal His-Leu dipeptide from angiotensin I to produce a potent vasopressor octapeptide, angiotensin II. Inhibitors of ACE are a first line of therapy for hypertension, heart failure, myocardial infarction and diabetic nephropathy. Notably, these inhibitors were developed without knowledge of the structure of human ACE, but were instead designed on the basis of an assumed mechanistic homology with carboxypeptidase A. Here we present the X-ray structure of human testicular ACE and its complex with one of the most widely used inhibitors, lisinopril (N2-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl-L-proline; also known as Prinivil or Zestril), at 2.0 A resolution. Analysis of the three-dimensional structure of ACE shows that it bears little similarity to that of carboxypeptidase A, but instead resembles neurolysin and Pyrococcus furiosus carboxypeptidase--zinc metallopeptidases with no detectable sequence similarity to ACE. The structure provides an opportunity to design domain-selective ACE inhibitors that may exhibit new pharmacological profiles.
  Selected figure(s)  
Figure 1.
Figure 1: Overview of tACE structure. a, Stereo view of the ribbon representation of the molecule looking down on the active site. The molecule can be divided into two portions, as subdomains I and II (cyan and pink, respectively). The active-site zinc ion and the lisinopril molecule are shown in green and yellow, respectively. The two chloride ions are shown as red spheres. b, Molecular surface representation (negative and positive potentials in red and blue, respectively) showing the active-site groove. The view is at 90 (towards the observer) to a. For clarity, the molecular surface has been sliced. The buried lisinopril molecule is shown in yellow. Helices 1, 2 and 3 forming the lid are shown. c, The structure -sequence relationship in tACE^10. The secondary structure elements (subdomain I in cyan; subdomain II in pink) follow the same colour code as in a. , -helices; , -strands; H, 3[10] helices. The important residues that are involved in binding are indicated as follows: zinc ligands, green boxes; chloride-binding residues, orange (Cl1) and red (Cl2) boxes; lisinopril-binding residues, yellow boxes; and glycosylation sites, black boxes.
Figure 2.
Figure 2: Details of the active site. a, Binding of lisinopril to tACE (stereo representation). Selected residues are shown in a 'ball-and-stick' representation with zinc atoms in green, chloride ions in red, water molecules in purple, and lisinopril (inhibitor) in yellow. Important secondary structure elements are marked. The lisinopril, Cl2, water hydrogen bonds and zinc coordination are shown in cyan, red, purple and green dotted lines, respectively. b, Schematic view of lisinopril binding with distances marked in . The different binding subsites are labelled.
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2003, 421, 551-554) copyright 2003.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
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21352096 M.Akif, S.L.Schwager, C.S.Anthony, B.Czarny, F.Beau, V.Dive, E.D.Sturrock, and K.R.Acharya (2011).
Novel mechanism of inhibition of human angiotensin-I-converting enzyme (ACE) by a highly specific phosphinic tripeptide.
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PDB codes: 2xy9 2xyd
21328404 V.Hähnke, A.Klenner, F.Rippmann, and G.Schneider (2011).
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20065150 E.G.Erdös, F.Tan, and R.A.Skidgel (2010).
Angiotensin I-converting enzyme inhibitors are allosteric enhancers of kinin B1 and B2 receptor function.
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Characterization of domain-selective inhibitor binding in angiotensin-converting enzyme using a novel derivative of lisinopril.
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PDB code: 3l3n
20454656 S.M.Danilov, S.Kalinin, Z.Chen, E.I.Vinokour, A.B.Nesterovitch, D.E.Schwartz, O.Gribouval, M.C.Gubler, and R.D.Minshall (2010).
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20030584 X.Sun, B.Rentzsch, M.Gong, J.Eichhorst, K.Pankow, G.Papsdorf, B.Maul, M.Bader, and W.E.Siems (2010).
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19552427 D.Xu, and H.Guo (2009).
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19188834 K.Hanif, Snehlata, M.C.Pavar, E.Arif, M.Fahim, M.A.Pasha, and S.Pasha (2009).
Effect of 3-thienylalanine-ornithine-proline, new sulfur-containing angiotensin-converting enzyme inhibitor on blood pressure and oxidative stress in spontaneously hypertensive rats.
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19685535 L.Hocharoen, and J.A.Cowan (2009).
Metallotherapeutics: novel strategies in drug design.
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19706421 M.Platten, S.Youssef, E.M.Hur, P.P.Ho, M.H.Han, T.V.Lanz, L.K.Phillips, M.J.Goldstein, R.Bhat, C.S.Raine, R.A.Sobel, and L.Steinman (2009).
Blocking angiotensin-converting enzyme induces potent regulatory T cells and modulates TH1- and TH17-mediated autoimmunity.
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18478260 M.Uematsu, O.Sakamoto, T.Ohura, N.Shimizu, K.Satomura, and S.Tsuchiya (2009).
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19551715 S.S.Vamvakas, L.Leondiadis, G.Pairas, E.Manessi-Zoupa, G.A.Spyroulias, and P.Cordopatis (2009).
Folding in solution of the C-catalytic protein fragment of angiotensin-converting enzyme.
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19307186 X.Liu, C.O.Bellamy, M.A.Bailey, L.J.Mullins, D.R.Dunbar, C.J.Kenyon, G.Brooker, S.Kantachuvesiri, K.Maratou, A.Ashek, A.F.Clark, S.Fleming, and J.J.Mullins (2009).
Angiotensin-converting enzyme is a modifier of hypertensive end organ damage.
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18563261 B.M.Liénard, G.Garau, L.Horsfall, A.I.Karsisiotis, C.Damblon, P.Lassaux, C.Papamicael, G.C.Roberts, M.Galleni, O.Dideberg, J.M.Frère, and C.J.Schofield (2008).
Structural basis for the broad-spectrum inhibition of metallo-beta-lactamases by thiols.
  Org Biomol Chem, 6, 2282-2294.
PDB codes: 2qds 2qdt
19021774 C.A.Rushworth, J.L.Guy, and A.J.Turner (2008).
Residues affecting the chloride regulation and substrate selectivity of the angiotensin-converting enzymes (ACE and ACE2) identified by site-directed mutagenesis.
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18539138 C.E.Isaza, X.Zhong, L.E.Rosas, J.D.White, R.P.Chen, G.F.Liang, S.I.Chan, A.R.Satoskar, and M.K.Chan (2008).
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Use of Fluorinated Functionality in Enzyme Inhibitor Development: Mechanistic and Analytical Advantages.
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Epitope mapping of mAbs to denatured human testicular ACE (CD143).
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18636749 S.Chattopadhyay, G.Karan, I.Sen, and G.C.Sen (2008).
A small region in the angiotensin-converting enzyme distal ectodomain is required for cleavage-secretion of the protein at the plasma membrane.
  Biochemistry, 47, 8335-8341.  
18400032 V.Rioli, B.C.Prezoto, K.Konno, R.L.Melo, C.F.Klitzke, E.S.Ferro, M.Ferreira-Lopes, A.C.Camargo, and F.C.Portaro (2008).
A novel bradykinin potentiating peptide isolated from Bothrops jararacussu venom using catallytically inactive oligopeptidase EP24.15.
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18443752 X.Z.Shen, H.D.Xiao, P.Li, C.X.Lin, S.Billet, D.Okwan-Duodu, J.W.Adams, E.A.Bernstein, Y.Xu, S.Fuchs, and K.E.Bernstein (2008).
New insights into the role of angiotensin-converting enzyme obtained from the analysis of genetically modified mice.
  J Mol Med, 86, 679-684.  
17257685 A.H.Danser, W.W.Batenburg, A.H.van den Meiracker, and S.M.Danilov (2007).
ACE phenotyping as a first step toward personalized medicine for ACE inhibitors. Why does ACE genotyping not predict the therapeutic efficacy of ACE inhibition?
  Pharmacol Ther, 113, 607-618.  
17441908 C.Falciani, L.Lozzi, A.Pini, F.Corti, M.Fabbrini, A.Bernini, B.Lelli, N.Niccolai, and L.Bracci (2007).
Molecular basis of branched peptides resistance to enzyme proteolysis.
  Chem Biol Drug Des, 69, 216-221.  
17251185 E.J.Lim, S.Sampath, J.Coll-Rodriguez, J.Schmidt, K.Ray, and D.W.Rodgers (2007).
Swapping the substrate specificities of the neuropeptidases neurolysin and thimet oligopeptidase.
  J Biol Chem, 282, 9722-9732.
PDB codes: 2o36 2o3e
17294247 I.Schellhammer, and M.Rarey (2007).
TrixX: structure-based molecule indexing for large-scale virtual screening in sublinear time.
  J Comput Aided Mol Des, 21, 223-238.  
17321748 M.L.Hemming, D.J.Selkoe, and W.Farris (2007).
Effects of prolonged angiotensin-converting enzyme inhibitor treatment on amyloid beta-protein metabolism in mouse models of Alzheimer disease.
  Neurobiol Dis, 26, 273-281.  
17722167 M.Losacco, R.Gallerani, M.Gobbetti, F.Minervini, and F.De Leo (2007).
Production of active angiotensin-I converting enzyme inhibitory peptides derived from bovine beta-casein by recombinant DNA technologies.
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17597519 M.Rella, J.L.Elliot, T.J.Revett, J.Lanfear, A.Phelan, R.M.Jackson, A.J.Turner, and N.M.Hooper (2007).
Identification and characterisation of the angiotensin converting enzyme-3 (ACE3) gene: a novel mammalian homologue of ACE.
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17878751 P.Daull, A.Y.Jeng, and B.Battistini (2007).
Towards triple vasopeptidase inhibitors for the treatment of cardiovascular diseases.
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16972307 S.S.Vamvakas, L.Leondiadis, G.Pairas, E.Manessi-Zoupa, G.A.Spyroulias, and P.Cordopatis (2007).
Expression, purification, and physicochemical characterization of the N-terminal active site of human angiotensin-I converting enzyme.
  J Pept Sci, 13, 31-36.  
17135201 Y.Wang, K.J.Addess, J.Chen, L.Y.Geer, J.He, S.He, S.Lu, T.Madej, A.Marchler-Bauer, P.A.Thiessen, N.Zhang, and S.H.Bryant (2007).
MMDB: annotating protein sequences with Entrez's 3D-structure database.
  Nucleic Acids Res, 35, D298-D300.  
16955069 B.Turk (2006).
Targeting proteases: successes, failures and future prospects.
  Nat Rev Drug Discov, 5, 785-799.  
17042482 J.M.Watermeyer, B.T.Sewell, S.L.Schwager, R.Natesh, H.R.Corradi, K.R.Acharya, and E.D.Sturrock (2006).
Structure of testis ACE glycosylation mutants and evidence for conserved domain movement.
  Biochemistry, 45, 12654-12663.
PDB codes: 2iul 2iux
17044798 M.R.Ehlers (2006).
Safety issues associated with the use of angiotensin-converting enzyme inhibitors.
  Expert Opin Drug Saf, 5, 739-740.  
16623712 N.D.Jullien, P.Cuniasse, D.Georgiadis, A.Yiotakis, and V.Dive (2006).
Combined use of selective inhibitors and fluorogenic substrates to study the specificity of somatic wild-type angiotensin-converting enzyme.
  FEBS J, 273, 1772-1781.  
16874470 N.H.Gokhale, and J.A.Cowan (2006).
Metallopeptide-promoted inactivation of angiotensin-converting enzyme and endothelin-converting enzyme 1: Toward dual-action therapeutics.
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16997139 P.J.Meek, Z.Liu, L.Tian, C.Y.Wang, W.J.Welsh, and R.J.Zauhar (2006).
Shape Signatures: speeding up computer aided drug discovery.
  Drug Discov Today, 11, 895-904.  
16606345 P.Redelinghuys, A.T.Nchinda, K.Chibale, and E.D.Sturrock (2006).
Novel ketomethylene inhibitors of angiotensin I-converting enzyme (ACE): inhibition and molecular modelling.
  Biol Chem, 387, 461-466.  
16403023 R.J.Bingham, V.Dive, S.E.Phillips, A.D.Shirras, and R.E.Isaac (2006).
Structural diversity of angiotensin-converting enzyme.
  FEBS J, 273, 362-373.  
16895474 Z.L.Woodman, S.L.Schwager, P.Redelinghuys, A.J.Chubb, E.L.van der Merwe, M.R.Ehlers, and E.D.Sturrock (2006).
Homologous substitution of ACE C-domain regions with N-domain sequences: effect on processing, shedding, and catalytic properties.
  Biol Chem, 387, 1043-1051.  
15883972 A.G.Tzakos, and I.P.Gerothanassis (2005).
Domain-selective ligand-binding modes and atomic level pharmacophore refinement in angiotensin I converting enzyme (ACE) inhibitors.
  Chembiochem, 6, 1089-1103.  
16342948 A.L.McClerren, S.Endsley, J.L.Bowman, N.H.Andersen, Z.Guan, J.Rudolph, and C.R.Raetz (2005).
A slow, tight-binding inhibitor of the zinc-dependent deacetylase LpxC of lipid A biosynthesis with antibiotic activity comparable to ciprofloxacin.
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16307311 D.J.Kuster, and G.R.Marshall (2005).
Validated ligand mapping of ACE active site.
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15665832 G.Kondoh, H.Tojo, Y.Nakatani, N.Komazawa, C.Murata, K.Yamagata, Y.Maeda, T.Kinoshita, M.Okabe, R.Taguchi, and J.Takeda (2005).
Angiotensin-converting enzyme is a GPI-anchored protein releasing factor crucial for fertilization.
  Nat Med, 11, 160-166.  
15785205 I.V.Balyasnikova, Z.L.Sun, F.E.Franke, Y.V.Berestetskaya, A.J.Chubb, R.F.Albrecht, E.D.Sturrock, and S.M.Danilov (2005).
Monoclonal antibodies 1B3 and 5C8 as probes for monitoring the integrity of the C-terminal end of soluble angiotensin-converting enzyme.
  Hybridoma (Larchmt), 24, 14-26.  
16008552 J.L.Guy, R.M.Jackson, H.A.Jensen, N.M.Hooper, and A.J.Turner (2005).
Identification of critical active-site residues in angiotensin-converting enzyme-2 (ACE2) by site-directed mutagenesis.
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16271036 N.A.Moiseeva, P.V.Binevski, I.I.Baskin, V.A.Palyulin, and O.A.Kost (2005).
Role of two chloride-binding sites in functioning of testicular angiotensin-converting enzyme.
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16317474 N.H.Gokhale, and J.A.Cowan (2005).
Inactivation of human angiotensin converting enzyme by copper peptide complexes containing ATCUN motifs.
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15615692 N.Naqvi, K.Liu, R.M.Graham, and A.Husain (2005).
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15692590 P.Corvol (2005).
ACE sets up fertilization.
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15702069 S.Mayor (2005).
ACEing GPI release.
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15994300 T.Suzuki, K.Ishihara, H.Migaki, K.Ishihara, M.Nagao, Y.Yamaguchi-Iwai, and T.Kambe (2005).
Two different zinc transport complexes of cation diffusion facilitator proteins localized in the secretory pathway operate to activate alkaline phosphatases in vertebrate cells.
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15525635 T.Suzuki, K.Ishihara, H.Migaki, W.Matsuura, A.Kohda, K.Okumura, M.Nagao, Y.Yamaguchi-Iwai, and T.Kambe (2005).
Zinc transporters, ZnT5 and ZnT7, are required for the activation of alkaline phosphatases, zinc-requiring enzymes that are glycosylphosphatidylinositol-anchored to the cytoplasmic membrane.
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15165741 A.J.Turner, J.A.Hiscox, and N.M.Hooper (2004).
ACE2: from vasopeptidase to SARS virus receptor.
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15508121 A.S.Galanis, G.A.Spyroulias, G.Pairas, E.Manessi-Zoupa, and P.Cordopatis (2004).
Solid-phase synthesis and conformational properties of angiotensin converting enzyme catalytic-site peptides: the basis for a structural study on the enzyme-substrate interaction.
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15337510 D.J.Burinsky, and S.L.Sides (2004).
Mass spectral fragmentation reactions of angiotensin-converting enzyme (ACE) inhibitors.
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14998993 K.Ray, C.S.Hines, J.Coll-Rodriguez, and D.W.Rodgers (2004).
Crystal structure of human thimet oligopeptidase provides insight into substrate recognition, regulation, and localization.
  J Biol Chem, 279, 20480-20489.
PDB code: 1s4b
15009531 N.Inguimbert, H.Poras, H.Dhotel, F.Beslot, E.Scalbert, C.Bennejean, P.Renard, M.C.Fournié-Zaluski, and B.P.Roques (2004).
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14754895 P.Towler, B.Staker, S.G.Prasad, S.Menon, J.Tang, T.Parsons, D.Ryan, M.Fisher, D.Williams, N.A.Dales, M.A.Patane, and M.W.Pantoliano (2004).
ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis.
  J Biol Chem, 279, 17996-18007.
PDB codes: 1r42 1r4l
12767125 A.S.Galanis, G.A.Spyroulias, R.Pierattelli, A.Tzakos, A.Troganis, I.P.Gerothanassis, G.Pairas, E.Manessi-Zoupa, and P.Cordopatis (2003).
Zinc binding in peptide models of angiotensin-I converting enzyme active sites studied through 1H-NMR and chemical shift perturbation mapping.
  Biopolymers, 69, 244-252.  
14559923 D.R.Brooks, P.J.Appleford, L.Murray, and R.E.Isaac (2003).
An essential role in molting and morphogenesis of Caenorhabditis elegans for ACN-1, a novel member of the angiotensin-converting enzyme family that lacks a metallopeptidase active site.
  J Biol Chem, 278, 52340-52346.  
12914653 J.F.Riordan (2003).
Angiotensin-I-converting enzyme and its relatives.
  Genome Biol, 4, 225.  
12915047 K.Brew (2003).
Structure of human ACE gives new insights into inhibitor binding and design.
  Trends Pharmacol Sci, 24, 391-394.  
14668810 K.R.Acharya, E.D.Sturrock, J.F.Riordan, and M.R.Ehlers (2003).
Ace revisited: a new target for structure-based drug design.
  Nat Rev Drug Discov, 2, 891-902.  
12832763 M.Selkti, A.Tomas, J.F.Gaucher, T.Prangé, M.C.Fournié-Zaluski, H.Chen, and B.P.Roques (2003).
Interactions of a new alpha-aminophosphinic derivative inside the active site of TLN (thermolysin): a model for zinc-metalloendopeptidase inhibition.
  Acta Crystallogr D Biol Crystallogr, 59, 1200-1205.
PDB codes: 1no0 1os0
12605218 N.M.Hooper, and A.J.Turner (2003).
An ACE structure.
  Nat Struct Biol, 10, 155-157.  
14526382 R.J.Lewis, and M.L.Garcia (2003).
Therapeutic potential of venom peptides.
  Nat Rev Drug Discov, 2, 790-802.  
12886014 S.Cal, V.Quesada, C.Garabaya, and C.Lopez-Otin (2003).
Polyserase-I, a human polyprotease with the ability to generate independent serine protease domains from a single translation product.
  Proc Natl Acad Sci U S A, 100, 9185-9190.  
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