1rhr
From Proteopedia
(New page: 200px<br /> <applet load="1rhr" size="450" color="white" frame="true" align="right" spinBox="true" caption="1rhr, resolution 3.00Å" /> '''CRYSTAL STRUCTURE O...) |
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| - | [[Image:1rhr.gif|left|200px]]<br /> | + | [[Image:1rhr.gif|left|200px]]<br /><applet load="1rhr" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1rhr" size=" | + | |
caption="1rhr, resolution 3.00Å" /> | caption="1rhr, resolution 3.00Å" /> | ||
'''CRYSTAL STRUCTURE OF THE COMPLEX OF CASPASE-3 WITH A CINNAMIC ACID METHYL ESTER INHIBITOR'''<br /> | '''CRYSTAL STRUCTURE OF THE COMPLEX OF CASPASE-3 WITH A CINNAMIC ACID METHYL ESTER INHIBITOR'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Caspases are cysteine proteases that specifically cleave Asp-Xxx bonds. | + | 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 Structure== | ==About this Structure== | ||
| - | 1RHR is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with CNE as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 1RHR is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=CNE:'>CNE</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1RHR OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
| - | [[Category: Becker, J | + | [[Category: Becker, J W.]] |
[[Category: Rotonda, J.]] | [[Category: Rotonda, J.]] | ||
| - | [[Category: Soisson, S | + | [[Category: Soisson, S M.]] |
[[Category: CNE]] | [[Category: CNE]] | ||
[[Category: apopain]] | [[Category: apopain]] | ||
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[[Category: yama]] | [[Category: yama]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:51:01 2008'' |
Revision as of 12:51, 21 February 2008
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CRYSTAL STRUCTURE OF THE COMPLEX OF CASPASE-3 WITH A CINNAMIC ACID METHYL ESTER INHIBITOR
Overview
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 Structure
1RHR is a Protein complex structure of sequences from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
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:15115390
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