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PDBsum entry 1yvb

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protein ligands Protein-protein interface(s) links
Hydrolase/hydrolase inhibitor PDB id
1yvb
Jmol
Contents
Protein chains
241 a.a. *
111 a.a. *
Ligands
GOL
Waters ×14
* Residue conservation analysis
PDB id:
1yvb
Name: Hydrolase/hydrolase inhibitor
Title: The plasmodium falciparum cysteine protease falcipain-2
Structure: Falcipain 2. Chain: a. Engineered: yes. Cystatin. Chain: i. Synonym: egg-white cystatin
Source: Plasmodium falciparum. Organism_taxid: 36329. Strain: 3d7. Gene: af239801. Expressed in: escherichia coli. Expression_system_taxid: 562. Gallus gallus. Chicken. Organism_taxid: 9031
Biol. unit: Dimer (from PQS)
Resolution:
2.70Å     R-factor:   0.232     R-free:   0.264
Authors: S.X.Wang
Key ref:
S.X.Wang et al. (2006). Structural basis for unique mechanisms of folding and hemoglobin binding by a malarial protease. Proc Natl Acad Sci U S A, 103, 11503-11508. PubMed id: 16864794 DOI: 10.1073/pnas.0600489103
Date:
15-Feb-05     Release date:   28-Mar-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q9N6S8  (Q9N6S8_PLAFA) -  Falcipain 2
Seq:
Struc:
484 a.a.
241 a.a.
Protein chain
Pfam   ArchSchema ?
P01038  (CYT_CHICK) -  Cystatin
Seq:
Struc:
139 a.a.
111 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   1 term 
  Biological process     proteolysis   3 terms 
  Biochemical function     peptidase inhibitor activity     3 terms  

 

 
DOI no: 10.1073/pnas.0600489103 Proc Natl Acad Sci U S A 103:11503-11508 (2006)
PubMed id: 16864794  
 
 
Structural basis for unique mechanisms of folding and hemoglobin binding by a malarial protease.
S.X.Wang, K.C.Pandey, J.R.Somoza, P.S.Sijwali, T.Kortemme, L.S.Brinen, R.J.Fletterick, P.J.Rosenthal, J.H.McKerrow.
 
  ABSTRACT  
 
Falcipain-2 (FP2), the major cysteine protease of the human malaria parasite Plasmodium falciparum, is a hemoglobinase and promising drug target. Here we report the crystal structure of FP2 in complex with a protease inhibitor, cystatin. The FP2 structure reveals two previously undescribed cysteine protease structural motifs, designated FP2(nose) and FP2(arm), in addition to details of the active site that will help focus inhibitor design. Unlike most cysteine proteases, FP2 does not require a prodomain but only the short FP2(nose) motif to correctly fold and gain catalytic activity. Our structure and mutagenesis data suggest a molecular basis for this unique mechanism by highlighting the functional role of two Tyr within FP2(nose) and a conserved Glu outside this motif. The FP2(arm) motif is required for hemoglobinase activity. The structure reveals topographic features and a negative charge cluster surrounding FP2(arm) that suggest it may serve as an exo-site for hemoglobin binding. Motifs similar to FP2(nose) and FP2(arm) are found only in related plasmodial proteases, suggesting that they confer malaria-specific functions.
 
  Selected figure(s)  
 
Figure 3.
Fig. 3. Structure and conservation of FP2 arm. (a) Putative arm regions from FP2-like cysteine proteases from five Plasmodium parasites are aligned by the ClustalW program. (b) 3F[o]–2F[c] electron density map of FP2[arm] rendered at 1.2 is depicted in stereoview. Electron densities surrounding FP2[arm] are contributed by FP2 residues from a neighboring symmetry mate (with carbons colored in white).
Figure 4.
Fig. 4. Active sites of FP2 versus papain complexed with protein and cathepsin V inhibitors. (a) FP2–cystatin, (b) papain–leupeptin (PDB ID code 1POP), and (c) cathepsin V-vinyl sulfone (PDB ID code 1FH0) are depicted in the same orientation. The catalytic Cys, His, and Asn are depicted in stick mode in green. Substrate-binding pockets are labeled P3 to P1'. The labels are positioned precisely in the same spacing to reflect the size differences of the substrate-binding pockets. Ile-68 is also depicted in stick mode to illustrate a slight protrusion in the S2 pocket of FP2.
 
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21429631 L.Rizzi, S.Sundararaman, K.Cendic, N.Vaiana, R.Korde, D.Sinha, A.Mohmmed, P.Malhotra, and S.Romeo (2011).
Design and synthesis of protein-protein interaction mimics as Plasmodium falciparum cysteine protease, falcipain-2 inhibitors.
  Eur J Med Chem, 46, 2083-2090.  
21275051 V.Ehmke, C.Heindl, M.Rottmann, C.Freymond, W.B.Schweizer, R.Brun, A.Stich, T.Schirmeister, and F.Diederich (2011).
Potent and Selective Inhibition of Cysteine Proteases from Plasmodium falciparum and Trypanosoma brucei.
  ChemMedChem, 6, 273-278.  
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.  
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
19128015 I.D.Kerr, J.H.Lee, K.C.Pandey, A.Harrison, M.Sajid, P.J.Rosenthal, and L.S.Brinen (2009).
Structures of falcipain-2 and falcipain-3 bound to small molecule inhibitors: implications for substrate specificity.
  J Med Chem, 52, 852-857.
PDB codes: 3bpf 3bpm
19479029 K.C.Pandey, D.T.Barkan, A.Sali, and P.J.Rosenthal (2009).
Regulatory elements within the prodomain of falcipain-2, a cysteine protease of the malaria parasite Plasmodium falciparum.
  PLoS One, 4, e5694.  
19357776 S.Subramanian, M.Hardt, Y.Choe, R.K.Niles, E.B.Johansen, J.Legac, J.Gut, I.D.Kerr, C.S.Craik, and P.J.Rosenthal (2009).
Hemoglobin cleavage site-specificity of the Plasmodium falciparum cysteine proteases falcipain-2 and falcipain-3.
  PLoS ONE, 4, e5156.  
17965183 F.P.Davis, D.T.Barkan, N.Eswar, J.H.McKerrow, and A.Sali (2007).
Host pathogen protein interactions predicted by comparative modeling.
  Protein Sci, 16, 2585-2596.  
17562535 F.Schulz, C.Gelhaus, B.Degel, R.Vicik, S.Heppner, A.Breuning, M.Leippe, J.Gut, P.J.Rosenthal, and T.Schirmeister (2007).
Screening of Protease Inhibitors as Antiplasmodial Agents. Part I: Aziridines and Epoxides.
  ChemMedChem, 2, 1214-1224.  
17875391 P.Gayathri, H.Balaram, and M.R.Murthy (2007).
Structural biology of plasmodial proteins.
  Curr Opin Struct Biol, 17, 744-754.  
17502099 S.X.Wang, K.C.Pandey, J.Scharfstein, J.Whisstock, R.K.Huang, J.Jacobelli, R.J.Fletterick, P.J.Rosenthal, M.Abrahamson, L.S.Brinen, A.Rossi, A.Sali, and J.H.McKerrow (2007).
The structure of chagasin in complex with a cysteine protease clarifies the binding mode and evolution of an inhibitor family.
  Structure, 15, 535-543.
PDB code: 2oul
17112720 P.R.Mittl, and M.G.Grütter (2006).
Opportunities for structure-based design of protease-directed drugs.
  Curr Opin Struct Biol, 16, 769-775.  
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.