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PDBsum entry 1er8
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Hydrolase PDB id
1er8

 

 

 

 

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Contents
Protein chain
330 a.a. *
Ligands
DHI-PRO-PHE-HIS-
LEU-LEU-VAL-TYR
Waters ×67
* Residue conservation analysis
PDB id:
1er8
Name: Hydrolase
Title: The active site of aspartic proteinases
Structure: Endothiapepsin. Chain: e. Synonym: aspartate protease. Engineered: yes. H-77. Chain: i. Engineered: yes
Source: Cryphonectria parasitica. Chesnut blight fungus. Organism_taxid: 5116. Gene: eapa, epn-1. Synthetic: yes
Biol. unit: Dimer (from PQS)
Resolution:
2.00Å     R-factor:   0.170    
Authors: A.M.Hemmings,B.Veerapandian,M.Szelke,J.B.Cooper,T.L.Blundell
Key ref: L.Pearl and T.Blundell (1984). The active site of aspartic proteinases. Febs Lett, 174, 96. PubMed id: 6381096
Date:
16-Oct-89     Release date:   15-Oct-91    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P11838  (CARP_CRYPA) -  Endothiapepsin from Cryphonectria parasitica
Seq:
Struc: 		419 a.a.
330 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.4.23.22  - endothiapepsin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Hydrolysis of proteins with broad specificity similar to that of pepsin A, preferring hydrophobic residues at P1 and P1', but does not cleave 14-Ala-|-Leu-15 in the B chain of insulin or Z-Glu-Tyr. Clots milk.

 

 
Febs Lett 174:96 (1984)
PubMed id: 6381096  
 
 
The active site of aspartic proteinases.
L.Pearl, T.Blundell.
 
  ABSTRACT  
 
The active site of the aspartic proteinase, endothiapepsin, has been defined by X-ray analysis and restrained least-squares refinement at 2.1 A resolution with a crystallographic agreement value of 0.16. The environments of the two catalytically important aspartyl groups are remarkably similar and the contributions of the NH2- and COOH-terminal domains to the catalytic centre are related by a local 2-fold axis. The carboxylates of the aspartyls share a hydrogen bond and have equivalent contacts to a bound water molecule or hydroxonium ion lying on the local diad. The main chains around 32 and 215 are connected by a novel interaction involving diad-related threonines. It is suggested that the two pKa values of the active site aspartyls arise from a structure not unlike that in maleic acid with a hydrogen-bonded intermediate species and a dicarboxylate characterised by electrostatic repulsions between the two negatively charged groups.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20524840 A.Kumar, S.Grover, J.Sharma, and V.K.Batish (2010).
Chymosin and other milk coagulants: sources and biotechnological interventions.
  Crit Rev Biotechnol, 30, 243-258.  
20376006 G.F.Schröder, M.Levitt, and A.T.Brunger (2010).
Super-resolution biomolecular crystallography with low-resolution data.
  Nature, 464, 1218-1222.  
19173708 C.Llorens, R.Futami, G.Renaud, and A.Moya (2009).
Bioinformatic flowchart and database to investigate the origins and diversity of Clan AA peptidases.
  Biol Direct, 4, 3.  
19285084 P.Bhaumik, H.Xiao, C.L.Parr, Y.Kiso, A.Gustchina, R.Y.Yada, and A.Wlodawer (2009).
Crystal structures of the histo-aspartic protease (HAP) from Plasmodium falciparum.
  J Mol Biol, 388, 520-540.
PDB codes: 3fns 3fnt 3fnu
18675276 A.S.Nascimento, S.Krauchenco, A.M.Golubev, A.Gustchina, A.Wlodawer, and I.Polikarpov (2008).
Statistical coupling analysis of aspartic proteinases based on crystal structures of the Trichoderma reesei enzyme and its complex with pepstatin A.
  J Mol Biol, 382, 763-778.
PDB codes: 3c9x 3c9y 3emy
17895280 C.Lloréns, R.Futami, D.Bezemer, and A.Moya (2008).
The Gypsy Database (GyDB) of mobile genetic elements.
  Nucleic Acids Res, 36, D38-D46.  
18498103 D.C.Bas, D.M.Rogers, and J.H.Jensen (2008).
Very fast prediction and rationalization of pKa values for protein-ligand complexes.
  Proteins, 73, 765-783.  
18378688 D.Imamura, R.Zhou, M.Feig, and L.Kroos (2008).
Evidence that the Bacillus subtilis SpoIIGA protein is a novel type of signal-transducing aspartic protease.
  J Biol Chem, 283, 15287-15299.  
17447722 C.L.Parr, R.A.Keates, B.C.Bryksa, M.Ogawa, and R.Y.Yada (2007).
The structure and function of Saccharomyces cerevisiae proteinase A.
  Yeast, 24, 467-480.  
  18084100 H.F.Tuan, P.Erskine, P.Langan, J.Cooper, and L.Coates (2007).
Preliminary neutron and ultrahigh-resolution X-ray diffraction studies of the aspartic proteinase endothiapepsin cocrystallized with a gem-diol inhibitor.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 1080-1083.  
17202208 M.S.Almeida, M.A.Johnson, T.Herrmann, M.Geralt, and K.Wüthrich (2007).
Novel beta-barrel fold in the nuclear magnetic resonance structure of the replicase nonstructural protein 1 from the severe acute respiratory syndrome coronavirus.
  J Virol, 81, 3151-3161.
PDB codes: 2gdt 2hsx
16673078 L.Coates, P.T.Erskine, S.Mall, R.Gill, S.P.Wood, D.A.Myles, and J.B.Cooper (2006).
X-ray, neutron and NMR studies of the catalytic mechanism of aspartic proteinases.
  Eur Biophys J, 35, 559-566.  
15229889 E.Alexov (2004).
Calculating proton uptake/release and binding free energy taking into account ionization and conformation changes induced by protein-inhibitor association: application to plasmepsin, cathepsin D and endothiapepsin-pepstatin complexes.
  Proteins, 56, 572-584.  
14500875 M.Ingr, T.Uhlíková, K.Strísovský, E.Majerová, and J.Konvalinka (2003).
Kinetics of the dimerization of retroviral proteases: the "fireman's grip" and dimerization.
  Protein Sci, 12, 2173-2182.  
12876323 P.T.Erskine, L.Coates, S.Mall, R.S.Gill, S.P.Wood, D.A.Myles, and J.B.Cooper (2003).
Atomic resolution analysis of the catalytic site of an aspartic proteinase and an unexpected mode of binding by short peptides.
  Protein Sci, 12, 1741-1749.
PDB codes: 1oew 1oex
12933791 R.Ishima, D.A.Torchia, S.M.Lynch, A.M.Gronenborn, and J.M.Louis (2003).
Solution structure of the mature HIV-1 protease monomer: insight into the tertiary fold and stability of a precursor.
  J Biol Chem, 278, 43311-43319.
PDB code: 1q9p
11807249 B.V.Prasad, and K.Suguna (2002).
Role of water molecules in the structure and function of aspartic proteinases.
  Acta Crystallogr D Biol Crystallogr, 58, 250-259.  
12393926 J.X.Yao (2002).
ACORN in CCP4 and its applications.
  Acta Crystallogr D Biol Crystallogr, 58, 1941-1947.  
10842341 C.M.Stultz, and M.Karplus (2000).
Dynamic ligand design and combinatorial optimization: designing inhibitors to endothiapepsin.
  Proteins, 40, 258-289.  
10666618 J.B.Cooper, and D.A.Myles (2000).
A preliminary neutron Laue diffraction study of the aspartic proteinase endothiapepsin.
  Acta Crystallogr D Biol Crystallogr, 56, 246-248.  
10957632 J.Foadi, M.M.Woolfson, E.J.Dodson, K.S.Wilson, Y.Jia-xing, and Z.Chao-de (2000).
A flexible and efficient procedure for the solution and phase refinement of protein structures.
  Acta Crystallogr D Biol Crystallogr, 56, 1137-1147.  
  11045610 K.Strisovsky, U.Tessmer, J.Langner, J.Konvalinka, and H.G.Kräusslich (2000).
Systematic mutational analysis of the active-site threonine of HIV-1 proteinase: rethinking the "fireman's grip" hypothesis.
  Protein Sci, 9, 1631-1641.  
10024021 J.V.Lehtonen, K.Denessiouk, A.C.May, and M.S.Johnson (1999).
Finding local structural similarities among families of unrelated protein structures: a generic non-linear alignment algorithm.
  Proteins, 34, 341-355.  
10194344 P.T.Erskine, E.Norton, J.B.Cooper, R.Lambert, A.Coker, G.Lewis, P.Spencer, M.Sarwar, S.P.Wood, M.J.Warren, and P.M.Shoolingin-Jordan (1999).
X-ray structure of 5-aminolevulinic acid dehydratase from Escherichia coli complexed with the inhibitor levulinic acid at 2.0 A resolution.
  Biochemistry, 38, 4266-4276.
PDB code: 1b4e
10450084 S.Hayward (1999).
Structural principles governing domain motions in proteins.
  Proteins, 36, 425-435.  
9485411 R.B.Rose, C.S.Craik, and R.M.Stroud (1998).
Domain flexibility in retroviral proteases: structural implications for drug resistant mutations.
  Biochemistry, 37, 2607-2621.
PDB code: 1az5
8778779 A.Beveridge (1996).
A theoretical study of torsional flexibility in the active site of aspartic proteinases: implications for catalysis.
  Proteins, 24, 322-334.  
8913621 G.Iliadis, B.Brzezinski, and G.Zundel (1996).
Aspartic proteinases: Fourier transform infrared spectroscopic studies of a model of the active side.
  Biophys J, 71, 2840-2847.  
8841139 R.B.Rose, C.S.Craik, N.L.Douglas, and R.M.Stroud (1996).
Three-dimensional structures of HIV-1 and SIV protease product complexes.
  Biochemistry, 35, 12933-12944.
PDB codes: 1ytg 1yth 1yti 1ytj
7650014 T.J.Cottrell, L.J.Harris, T.Tanaka, and R.Y.Yada (1995).
The sole lysine residue in porcine pepsin works as a key residue for catalysis and conformational flexibility.
  J Biol Chem, 270, 19974-19978.  
  7756993 A.A.Adzhubei, and M.J.Sternberg (1994).
Conservation of polyproline II helices in homologous proteins: implications for structure prediction by model building.
  Protein Sci, 3, 2395-2410.  
8122962 M.Lang, and J.Roesel (1993).
HIV-1 protease inhibitors: development, status, and potential role in the treatment of AIDS.
  Arch Pharm (Weinheim), 326, 921-924.  
8464727 S.L.Moodie, and J.M.Thornton (1993).
A study into the effects of protein binding on nucleotide conformation.
  Nucleic Acids Res, 21, 1369-1380.  
  8302216 W.G.Dougherty, and B.L.Semler (1993).
Expression of virus-encoded proteinases: functional and structural similarities with cellular enzymes.
  Microbiol Rev, 57, 781-822.  
1603805 A.Sali, B.Veerapandian, J.B.Cooper, D.S.Moss, T.Hofmann, and T.L.Blundell (1992).
Domain flexibility in aspartic proteinases.
  Proteins, 12, 158-170.  
  1304340 B.Veerapandian, J.B.Cooper, A.Sali, T.L.Blundell, R.L.Rosati, B.W.Dominy, D.B.Damon, and D.J.Hoover (1992).
Direct observation by X-ray analysis of the tetrahedral "intermediate" of aspartic proteinases.
  Protein Sci, 1, 322-328.
PDB code: 1epo
1332025 D.H.Ohlendorf, S.I.Foundling, J.J.Wendoloski, J.Sedlacek, P.Strop, and F.R.Salemme (1992).
Structural studies of the retroviral proteinase from avian myeloblastosis associated virus.
  Proteins, 14, 382-391.
PDB codes: 1mvp 2mvp
  1304887 E.Meyer (1992).
Internal water molecules and H-bonding in biological macromolecules: a review of structural features with functional implications.
  Protein Sci, 1, 1543-1562.  
1594574 J.A.Hartsuck, G.Koelsch, and S.J.Remington (1992).
The high-resolution crystal structure of porcine pepsinogen.
  Proteins, 13, 1.
PDB code: 3psg
  1874000 C.Hutchins, and J.Greer (1991).
Comparative modeling of proteins in the design of novel renin inhibitors.
  Crit Rev Biochem Mol Biol, 26, 77.  
2217166 G.L.Gilliland, E.L.Winborne, J.Nachman, and A.Wlodawer (1990).
The three-dimensional structure of recombinant bovine chymosin at 2.3 A resolution.
  Proteins, 8, 82.
PDB code: 1cms
2153583 J.K.Rao, and A.Wlodawer (1990).
Is the pseudo-dyad in retroviral proteinase monomers structural or evolutionary?
  FEBS Lett, 260, 201-205.  
2182390 R.M.Berka, M.Ward, L.J.Wilson, K.J.Hayenga, K.H.Kodama, L.P.Carlomagno, and S.A.Thompson (1990).
Molecular cloning and deletion of the gene encoding aspergillopepsin A from Aspergillus awamori.
  Gene, 86, 153-162.  
2078031 T.D.Meek, and G.B.Dreyer (1990).
HIV-1 protease as a potential target for anti-AIDS therapy.
  Ann N Y Acad Sci, 616, 41-53.  
2278102 T.L.Blundell, R.Lapatto, A.F.Wilderspin, A.M.Hemmings, P.M.Hobart, D.E.Danley, and P.J.Whittle (1990).
The 3-D structure of HIV-1 proteinase and the design of antiviral agents for the treatment of AIDS.
  Trends Biochem Sci, 15, 425-430.  
2184298 W.J.Greenlee (1990).
Renin inhibitors.
  Med Res Rev, 10, 173-236.  
  2676515 A.Sali, B.Veerapandian, J.B.Cooper, S.I.Foundling, D.J.Hoover, and T.L.Blundell (1989).
High-resolution X-ray diffraction study of the complex between endothiapepsin and an oligopeptide inhibitor: the analysis of the inhibitor binding and description of the rigid body shift in the enzyme.
  EMBO J, 8, 2179-2188.
PDB code: 5er2
3119339 J.Cooper, S.Foundling, A.Hemmings, T.Blundell, D.M.Jones, A.Hallett, and M.Szelke (1987).
The structure of a synthetic pepsin inhibitor complexed with endothiapepsin.
  Eur J Biochem, 169, 215-221.
PDB code: 2er6
3546346 J.Tang, and R.N.Wong (1987).
Evolution in the structure and function of aspartic proteases.
  J Cell Biochem, 33, 53-63.  
3313384 K.Suguna, E.A.Padlan, C.W.Smith, W.D.Carlson, and D.R.Davies (1987).
Binding of a reduced peptide inhibitor to the aspartic proteinase from Rhizopus chinensis: implications for a mechanism of action.
  Proc Natl Acad Sci U S A, 84, 7009-7013.
PDB code: 3apr
3305016 V.Barkholt (1987).
Amino acid sequence of endothiapepsin. Complete primary structure of the aspartic protease from Endothia parasitica.
  Eur J Biochem, 167, 327-338.  
2872673 G.A.Scarborough (1986).
A chemically explicit model for the molecular mechanism of the F1F0 H+-ATPase/ATP synthases.
  Proc Natl Acad Sci U S A, 83, 3688-3692.  
6432579 B.L.Sibanda, T.Blundell, P.M.Hobart, M.Fogliano, J.S.Bindra, B.W.Dominy, and J.M.Chirgwin (1984).
Computer graphics modelling of human renin. Specificity, catalytic activity and intron-exon junctions.
  FEBS Lett, 174, 102-111.  
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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