spacer
spacer

PDBsum entry 1aim
Go to PDB code: 
protein ligands links
Hydrolase/hydrolase inhibitor PDB id
1aim

 

 

 

 

Loading ...

 
JSmol PyMol  
Contents
Protein chain
215 a.a. *
Ligands
ZYA
Waters ×138
* Residue conservation analysis
PDB id:
1aim
Name: Hydrolase/hydrolase inhibitor
Title: Cruzain inhibited by benzoyl-tyrosine-alanine-fluoromethylketone
Structure: Cruzain. Chain: a. Fragment: catalytic domain. Engineered: yes. Mutation: yes
Source: Trypanosoma cruzi. Organism_taxid: 5693. Gene: rtp. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
2.00Å     R-factor:   0.188     R-free:   0.247
Authors: R.Fletterick,S.Gillmor
Key ref: S.A.Gillmor et al. (1997). Structural determinants of specificity in the cysteine protease cruzain. Protein Sci, 6, 1603-1611. PubMed id: 9260273 DOI: 10.1002/pro.5560060801
Date:
21-Apr-97     Release date:   22-Oct-97    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P25779  (CYSP_TRYCR) -  Cruzipain from Trypanosoma cruzi
Seq:
Struc: 		467 a.a.
215 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.3.4.22.51  - cruzipain.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

 

 
DOI no: 10.1002/pro.5560060801 Protein Sci 6:1603-1611 (1997)
PubMed id: 9260273  
 
 
Structural determinants of specificity in the cysteine protease cruzain.
S.A.Gillmor, C.S.Craik, R.J.Fletterick.
 
  ABSTRACT  
 
The structure of cruzain, an essential protease from the parasite Trypanosoma cruzi, was determined by X-ray crystallography bound to two different covalent inhibitors. The cruzain S2 specificity pocket is able to productively bind both arginine and phenylalanine residues. The structures of cruzain bound to benzoyl-Arg-Ala-fluoromethyl ketone and benzoyl-Tyr-Ala-fluoromethyl ketone at 2.2 and 2.1 A, respectively, show a pH-dependent specificity switch. Glu 205 adjusts to restructure the S2 specificity pocket, conferring right binding to both hydrophobic and basic residues. Kinetic analysis of activated peptide substrates shows that substrates placing hydrophobic residues in the specificity pocket are cleaved at a broader pH range than hydrophilic substrates. These results demonstrate how cruzain binds both basic and hydrophobic residues and could be important for in vivo regulation of cruzain activity.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21360607 H.C.Castro, P.A.Abreu, R.B.Geraldo, R.C.Martins, R.Dos Santos, N.I.Loureiro, L.M.Cabral, and C.R.Rodrigues (2011).
Looking at the proteases from a simple perspective.
  J Mol Recognit, 24, 165-181.  
20967286 B.K.Na, Y.A.Bae, Y.G.Zo, Y.Choe, S.H.Kim, P.V.Desai, M.A.Avery, C.S.Craik, T.S.Kim, P.J.Rosenthal, and Y.Kong (2010).
Biochemical properties of a novel cysteine protease of Plasmodium vivax, vivapain-4.
  PLoS Negl Trop Dis, 4, e849.  
20485483 J.D.Durrant, H.Keränen, B.A.Wilson, and J.A.McCammon (2010).
Computational identification of uncharacterized cruzain binding sites.
  PLoS Negl Trop Dis, 4, e676.  
20088534 K.Brak, I.D.Kerr, K.T.Barrett, N.Fuchi, M.Debnath, K.Ang, J.C.Engel, J.H.McKerrow, P.S.Doyle, L.S.Brinen, and J.A.Ellman (2010).
Nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors as promising new leads for Chagas disease chemotherapy.
  J Med Chem, 53, 1763-1773.
PDB code: 3iut
20540517 R.S.Ferreira, A.Simeonov, A.Jadhav, O.Eidam, B.T.Mott, M.J.Keiser, J.H.McKerrow, D.J.Maloney, J.J.Irwin, and B.K.Shoichet (2010).
Complementarity between a docking and a high-throughput screen in discovering new cruzain inhibitors.
  J Med Chem, 53, 4891-4905.
PDB code: 3kku
  20856868 Y.T.Chen, L.S.Brinen, I.D.Kerr, E.Hansell, P.S.Doyle, J.H.McKerrow, and W.R.Roush (2010).
In vitro and in vivo studies of the trypanocidal properties of WRR-483 against Trypanosoma cruzi.
  PLoS Negl Trop Dis, 4, 0.
PDB code: 3lxs
19620707 I.D.Kerr, J.H.Lee, C.J.Farady, R.Marion, M.Rickert, M.Sajid, K.C.Pandey, C.R.Caffrey, J.Legac, E.Hansell, J.H.McKerrow, C.S.Craik, P.J.Rosenthal, and L.S.Brinen (2009).
Vinyl sulfones as antiparasitic agents and a structural basis for drug design.
  J Biol Chem, 284, 25697-25703.
PDB codes: 2oz2 2p7u 3bwk
18294123 G.N.Rudenskaya, and D.V.Pupov (2008).
Cysteine proteinases of microorganisms and viruses.
  Biochemistry (Mosc), 73, 1.  
18979626 J.Scharfstein, A.C.Monteiro, V.Schmitz, and E.Svensjö (2008).
Angiotensin-converting enzyme limits inflammation elicited by Trypanosoma cruzi cysteine proteases: a peripheral mechanism regulating adaptive immunity via the innate kinin pathway.
  Biol Chem, 389, 1015-1024.  
18445589 K.N.DuBois, M.Abodeely, J.Sakanari, C.S.Craik, M.Lee, J.H.McKerrow, and M.Sajid (2008).
Identification of the major cysteine protease of Giardia and its role in encystation.
  J Biol Chem, 283, 18024-18031.  
17935329 S.Ma, L.S.Devi-Kesavan, and J.Gao (2007).
Molecular dynamics simulations of the catalytic pathway of a cysteine protease: a combined QM/MM study of human cathepsin K.
  J Am Chem Soc, 129, 13633-13645.  
14694194 M.Zhu, F.Shao, R.W.Innes, J.E.Dixon, and Z.Xu (2004).
The crystal structure of Pseudomonas avirulence protein AvrPphB: a papain-like fold with a distinct substrate-binding site.
  Proc Natl Acad Sci U S A, 101, 302-307.
PDB code: 1ukf
15009216 W.A.Judice, L.Puzer, S.S.Cotrin, A.K.Carmona, G.H.Coombs, L.Juliano, and M.A.Juliano (2004).
Carboxydipeptidase activities of recombinant cysteine peptidases. Cruzain of Trypanosoma cruzi and CPB of Leishmania mexicana.
  Eur J Biochem, 271, 1046-1053.  
12887059 C.Serveau, A.Boulangé, F.Lecaille, F.Gauthier, E.Authié, and G.Lalmanach (2003).
Procongopain from Trypanosoma congolense is processed at basic pH: an unusual feature among cathepsin L-like cysteine proteases.
  Biol Chem, 384, 921-927.  
12833545 M.Sulpizi, A.Laio, J.VandeVondele, A.Cattaneo, U.Rothlisberger, and P.Carloni (2003).
Reaction mechanism of caspases: insights from QM/MM Car-Parrinello simulations.
  Proteins, 52, 212-224.  
12668429 M.Sulpizi, U.Rothlisberger, and P.Carloni (2003).
Molecular dynamics studies of caspase-3.
  Biophys J, 84, 2207-2215.  
12592020 Y.A.Sabnis, P.V.Desai, P.J.Rosenthal, and M.A.Avery (2003).
Probing the structure of falcipain-3, a cysteine protease from Plasmodium falciparum: comparative protein modeling and docking studies.
  Protein Sci, 12, 501-509.  
12142451 D.J.Rigden, V.V.Mosolov, and M.Y.Galperin (2002).
Sequence conservation in the chagasin family suggests a common trend in cysteine proteinase binding by unrelated protein inhibitors.
  Protein Sci, 11, 1971-1977.  
12108538 G.Lalmanach, A.Boulangé, C.Serveau, F.Lecaille, J.Scharfstein, F.Gauthier, and E.Authié (2002).
Congopain from Trypanosoma congolense: drug target and vaccine candidate.
  Biol Chem, 383, 739-749.  
12045098 M.Klemba, and D.E.Goldberg (2002).
Biological roles of proteases in parasitic protozoa.
  Annu Rev Biochem, 71, 275-305.  
11322895 F.Lecaille, E.Authié, T.Moreau, C.Serveau, F.Gauthier, and G.Lalmanach (2001).
Subsite specificity of trypanosomal cathepsin L-like cysteine proteases. Probing the S2 pocket with phenylalanine-derived amino acids.
  Eur J Biochem, 268, 2733-2741.  
11231271 L.C.Alves, R.L.Melo, S.J.Sanderson, J.C.Mottram, G.H.Coombs, G.Caliendo, V.Santagada, L.Juliano, and M.A.Juliano (2001).
S1 subsite specificity of a recombinant cysteine proteinase, CPB, of Leishmania mexicana compared with cruzain, human cathepsin L and papain using substrates containing non-natural basic amino acids.
  Eur J Biochem, 268, 1206-1212.  
11389727 L.Salvati, M.Mattu, F.Polticelli, F.Tiberi, L.Gradoni, G.Venturini, M.Bolognesi, and P.Ascenzi (2001).
Modulation of the catalytic activity of cruzipain, the major cysteine proteinase from Trypanosoma cruzi, by temperature and pH.
  Eur J Biochem, 268, 3253-3258.  
11737212 W.A.Judice, M.H.Cezari, A.P.Lima, J.Scharfstein, J.R.Chagas, I.L.Tersariol, M.A.Juliano, and L.Juliano (2001).
Comparison of the specificity, stability and individual rate constants with respective activation parameters for the peptidase activity of cruzipain and its recombinant form, cruzain, from Trypanosoma cruzi.
  Eur J Biochem, 268, 6578-6586.  
10997902 L.S.Brinen, E.Hansell, J.Cheng, W.R.Roush, J.H.McKerrow, and R.J.Fletterick (2000).
A target within the target: probing cruzain's P1' site to define structural determinants for the Chagas' disease protease.
  Structure, 8, 831-840.
PDB codes: 1f29 1f2a 1f2b 1f2c
10971478 R.Furmonaviciene, H.F.Sewell, and F.Shakib (2000).
Comparative molecular modelling identifies a common putative IgE epitope on cysteine protease allergens of diverse sources.
  Clin Exp Allergy, 30, 1307-1313.  
10980453 X.Du, E.Hansell, J.C.Engel, C.R.Caffrey, F.E.Cohen, and J.H.McKerrow (2000).
Aryl ureas represent a new class of anti-trypanosomal agents.
  Chem Biol, 7, 733-742.  
9914503 C.Serveau, G.Lalmanach, I.Hirata, J.Scharfstein, M.A.Juliano, and F.Gauthier (1999).
Discrimination of cruzipain, the major cysteine proteinase of Trypanosoma cruzi, and mammalian cathepsins B and L, by a pH-inducible fluorogenic substrate of trypanosomal cysteine proteinases.
  Eur J Biochem, 259, 275-280.  
10410800 M.E.McGrath (1999).
The lysosomal cysteine proteases.
  Annu Rev Biophys Biomol Struct, 28, 181-204.  
  9524065 D.Turk, G.Guncar, M.Podobnik, and B.Turk (1998).
Revised definition of substrate binding sites of papain-like cysteine proteases.
  Biol Chem, 379, 137-147.  
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.

 

spacer
spacer