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Hydrolase PDB id
1rhm
Jmol
Contents
Protein chains
140 a.a. *
91 a.a. *
Ligands
NA4 ×2
Waters ×167
* Residue conservation analysis
PDB id:
1rhm
Name: Hydrolase
Title: Crystal structure of the complex of caspase-3 with a nicotinic acid aldehyde inhibitor
Structure: Casp-3. Chain: a, c. Fragment: p17 subunit. Synonym: cysteine protease cpp32, yama protein, cpp-32, caspase-3, apopain, srebp cleavage activity 1, sca-1. Engineered: yes. Casp-3. Chain: b, d. Fragment: p12 subunit.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: casp3, cpp32. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Tetramer (from PQS)
Resolution:
2.50Å     R-factor:   0.192     R-free:   0.249
Authors: J.W.Becker,J.Rotonda,S.M.Soisson
Key ref: J.W.Becker et al. (2004). Reducing the peptidyl features of caspase-3 inhibitors: a structural analysis. J Med Chem, 47, 2466-2474. PubMed id: 15115390 DOI: 10.1021/jm0305523
Date:
14-Nov-03     Release date:   11-May-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P42574  (CASP3_HUMAN) -  Caspase-3
Seq:
Struc: 		277 a.a.
140 a.a.
Protein chains
Pfam   ArchSchema ?
P42574  (CASP3_HUMAN) -  Caspase-3
Seq:
Struc: 		277 a.a.
91 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains A, B, C, D: E.C.3.4.22.56  - Caspase-3.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cytoplasm   1 term 
  Biological process     apoptosis   2 terms 
  Biochemical function     cysteine-type peptidase activity     2 terms  

 

 
DOI no: 10.1021/jm0305523 J Med Chem 47:2466-2474 (2004)
PubMed id: 15115390  
 
 
Reducing the peptidyl features of caspase-3 inhibitors: a structural analysis.
J.W.Becker, J.Rotonda, S.M.Soisson, R.Aspiotis, C.Bayly, S.Francoeur, M.Gallant, M.Garcia-Calvo, A.Giroux, E.Grimm, Y.Han, D.McKay, D.W.Nicholson, E.Peterson, J.Renaud, S.Roy, N.Thornberry, R.Zamboni.
 
  ABSTRACT  
 
Caspases are cysteine proteases that specifically cleave Asp-Xxx bonds. They are key agents in inflammation and apoptosis and are attractive targets for therapy against inflammation, neurodegeneration, ischemia, and cancer. Many caspase structures are known, but most involve either peptide or protein inhibitors, unattractive candidates for drug development. We present seven crystal structures of inhibited caspase-3 that illustrate several approaches to reducing the peptidyl characteristics of the inhibitors while maintaining their potency and selectivity. The inhibitors reduce the peptidyl nature of inhibitors while preserving binding potency by (1). exploiting a hydrophobic binding site C-terminal to the cleavage site, (2). replacing the negatively charged aspartyl residue at P4 with neutral groups, and (3). using a peptidomimetic 5,6,7-tricyclic system or a pyrazinone at P2-P3. In addition, we have found that two nicotinic acid aldehydes induce a significant conformational change in the S2 and S3 subsites of caspase-3, revealing an unexpected binding mode. These results advance the search for caspase-directed drugs by revealing how unacceptable molecular features can be removed without loss of potency.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19918833 P.Reszka, R.Schulz, K.Methling, M.Lalk, and P.J.Bednarski (2010).
Synthesis, enzymatic evaluation, and docking studies of fluorogenic caspase 8 tetrapeptide substrates.
  ChemMedChem, 5, 103-117.  
20799349 S.C.Sukuru, F.Nigsch, J.Quancard, M.Renatus, R.Chopra, N.Brooijmans, D.Mikhailov, Z.Deng, A.Cornett, J.L.Jenkins, U.Hommel, J.W.Davies, and M.Glick (2010).
A lead discovery strategy driven by a comprehensive analysis of proteases in the peptide substrate space.
  Protein Sci, 19, 2096-2109.  
19610597 Q.Wang, R.H.Mach, and D.E.Reichert (2009).
Docking and 3D-QSAR studies on isatin sulfonamide analogues as caspase-3 inhibitors.
  J Chem Inf Model, 49, 1963-1973.  
18768468 J.Q.Du, J.Wu, H.J.Zhang, Y.H.Zhang, B.Y.Qiu, F.Wu, Y.H.Chen, J.Y.Li, F.J.Nan, J.P.Ding, and J.Li (2008).
Isoquinoline-1,3,4-trione Derivatives Inactivate Caspase-3 by Generation of Reactive Oxygen Species.
  J Biol Chem, 283, 30205-30215.
PDB codes: 3deh 3dei 3dej 3dek
18292873 S.L.Ng, P.Y.Yang, K.Y.Chen, R.Srinivasan, and S.Q.Yao (2008).
"Click" synthesis of small-molecule inhibitors targeting caspases.
  Org Biomol Chem, 6, 844-847.  
18265412 Y.Shimmyo, T.Kihara, A.Akaike, T.Niidome, and H.Sugimoto (2008).
Three distinct neuroprotective functions of myricetin against glutamate-induced neuronal cell death: involvement of direct inhibition of caspase-3.
  J Neurosci Res, 86, 1836-1845.  
17594508 A.Yoshimori, J.Sakai, S.Sunaga, T.Kobayashi, S.Takahashi, N.Okita, R.Takasawa, and S.Tanuma (2007).
Structural and functional definition of the specificity of a novel caspase-3 inhibitor, Ac-DNLD-CHO.
  BMC Pharmacol, 7, 8.  
16892093 L.Galluzzi, N.Larochette, N.Zamzami, and G.Kroemer (2006).
Mitochondria as therapeutic targets for cancer chemotherapy.
  Oncogene, 25, 4812-4830.  
16151634 S.Matza-Porges, I.Horresh, E.Tavor, A.Panet, and A.Honigman (2005).
Expression of an anti apoptotic recombinant short peptide in mammalian cells.
  Apoptosis, 10, 987-996.  
15665817 U.Fischer, and K.Schulze-Osthoff (2005).
Apoptosis-based therapies and drug targets.
  Cell Death Differ, 12, 942-961.  
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.