1re1: Difference between revisions
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[[Image:1re1.gif|left|200px]] | [[Image:1re1.gif|left|200px]] | ||
'''CRYSTAL STRUCTURE OF CASPASE-3 WITH A NICOTINIC ACID ALDEHYDE INHIBITOR''' | {{Structure | ||
|PDB= 1re1 |SIZE=350|CAPTION= <scene name='initialview01'>1re1</scene>, resolution 2.50Å | |||
|SITE= | |||
|LIGAND= <scene name='pdbligand=NA3:(3S)-3-{[(5-BROMOPYRIDIN-3-YL)CARBONYL]AMINO}-4-OXOBUTANOIC ACID'>NA3</scene> | |||
|ACTIVITY= | |||
|GENE= CASP3, CPP32 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |||
}} | |||
'''CRYSTAL STRUCTURE OF CASPASE-3 WITH A NICOTINIC ACID ALDEHYDE INHIBITOR''' | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
1RE1 is a [ | 1RE1 is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1RE1 OCA]. | ||
==Reference== | ==Reference== | ||
Reducing the peptidyl features of caspase-3 inhibitors: a structural analysis., Becker JW, Rotonda J, Soisson SM, Aspiotis R, Bayly C, Francoeur S, Gallant M, Garcia-Calvo M, Giroux A, Grimm E, Han Y, McKay D, Nicholson DW, Peterson E, Renaud J, Roy S, Thornberry N, Zamboni R, J Med Chem. 2004 May 6;47(10):2466-74. PMID:[http:// | Reducing the peptidyl features of caspase-3 inhibitors: a structural analysis., Becker JW, Rotonda J, Soisson SM, Aspiotis R, Bayly C, Francoeur S, Gallant M, Garcia-Calvo M, Giroux A, Grimm E, Han Y, McKay D, Nicholson DW, Peterson E, Renaud J, Roy S, Thornberry N, Zamboni R, J Med Chem. 2004 May 6;47(10):2466-74. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15115390 15115390] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
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[[Category: yama]] | [[Category: yama]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 13:50:19 2008'' | ||
Revision as of 14:50, 20 March 2008
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| , resolution 2.50Å | |||||||
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| Ligands: | |||||||
| Gene: | CASP3, CPP32 (Homo sapiens) | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
CRYSTAL STRUCTURE OF CASPASE-3 WITH A NICOTINIC ACID ALDEHYDE INHIBITOR
OverviewOverview
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.
About this StructureAbout this Structure
1RE1 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Reducing the peptidyl features of caspase-3 inhibitors: a structural analysis., Becker JW, Rotonda J, Soisson SM, Aspiotis R, Bayly C, Francoeur S, Gallant M, Garcia-Calvo M, Giroux A, Grimm E, Han Y, McKay D, Nicholson DW, Peterson E, Renaud J, Roy S, Thornberry N, Zamboni R, J Med Chem. 2004 May 6;47(10):2466-74. PMID:15115390
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