2gpl
From Proteopedia
(New page: 200px<br /><applet load="2gpl" size="450" color="white" frame="true" align="right" spinBox="true" caption="2gpl, resolution 2.81Å" /> '''TMC-95 based bipheny...) |
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| - | [[Image:2gpl.gif|left|200px]]<br /><applet load="2gpl" size=" | + | [[Image:2gpl.gif|left|200px]]<br /><applet load="2gpl" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="2gpl, resolution 2.81Å" /> | caption="2gpl, resolution 2.81Å" /> | ||
'''TMC-95 based biphenyl-ether macrocycles: specific proteasome inhibitors'''<br /> | '''TMC-95 based biphenyl-ether macrocycles: specific proteasome inhibitors'''<br /> | ||
==Overview== | ==Overview== | ||
| - | TMC-95's natural cyclic tripeptide metabolites represent potent | + | TMC-95's natural cyclic tripeptide metabolites represent potent competitive proteasome inhibitors. The constrained conformation of TMC-95 proteasomal inhibitors provides the driving force for entropically high-affinity binding. Based on the crystal structure of the proteasome:TMC-95A complex, the synthetically challenging TMC-95 core structure was used for the design and synthesis of less demanding biphenyl-ether macrocycles, in which the biphenyl-ether moiety functions as an endocyclic clamp restricting its tripeptide backbone. These simplified analogs allowed us to identify high plasticity of the proteasomal tryptic-like specificity pocket. Biphenyl-ether compounds extended with an amide group were hydrolyzed by the proteasome, although the crystal structure of such proteasome:biphenyl-ether complexes revealed quenching of proteolysis at the acyl-enzyme intermediate. Our data reveal that biphenyl-ether derivatives bind noncovalently to the proteasomal tryptic-like active site in a reversible substrate-like manner without allosteric changes of active site residues. |
==About this Structure== | ==About this Structure== | ||
| - | 2GPL is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae] with BIQ as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Proteasome_endopeptidase_complex Proteasome endopeptidase complex], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.25.1 3.4.25.1] Full crystallographic information is available from [http:// | + | 2GPL is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae] with <scene name='pdbligand=BIQ:'>BIQ</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Proteasome_endopeptidase_complex Proteasome endopeptidase complex], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.25.1 3.4.25.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GPL OCA]. |
==Reference== | ==Reference== | ||
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[[Category: proteasomal subunit fold represents an antiparallel beta-sheet flanked by helices; ntn-hydrolase]] | [[Category: proteasomal subunit fold represents an antiparallel beta-sheet flanked by helices; ntn-hydrolase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:33:59 2008'' |
Revision as of 15:34, 21 February 2008
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TMC-95 based biphenyl-ether macrocycles: specific proteasome inhibitors
Overview
TMC-95's natural cyclic tripeptide metabolites represent potent competitive proteasome inhibitors. The constrained conformation of TMC-95 proteasomal inhibitors provides the driving force for entropically high-affinity binding. Based on the crystal structure of the proteasome:TMC-95A complex, the synthetically challenging TMC-95 core structure was used for the design and synthesis of less demanding biphenyl-ether macrocycles, in which the biphenyl-ether moiety functions as an endocyclic clamp restricting its tripeptide backbone. These simplified analogs allowed us to identify high plasticity of the proteasomal tryptic-like specificity pocket. Biphenyl-ether compounds extended with an amide group were hydrolyzed by the proteasome, although the crystal structure of such proteasome:biphenyl-ether complexes revealed quenching of proteolysis at the acyl-enzyme intermediate. Our data reveal that biphenyl-ether derivatives bind noncovalently to the proteasomal tryptic-like active site in a reversible substrate-like manner without allosteric changes of active site residues.
About this Structure
2GPL is a Protein complex structure of sequences from Saccharomyces cerevisiae with as ligand. Active as Proteasome endopeptidase complex, with EC number 3.4.25.1 Full crystallographic information is available from OCA.
Reference
TMC-95-based inhibitor design provides evidence for the catalytic versatility of the proteasome., Groll M, Gotz M, Kaiser M, Weyher E, Moroder L, Chem Biol. 2006 Jun;13(6):607-14. PMID:16793518
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