2gpl: Difference between revisions

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[[Image:2gpl.gif|left|200px]]
{{Seed}}
[[Image:2gpl.png|left|200px]]


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{{STRUCTURE_2gpl|  PDB=2gpl  |  SCENE=  }}  
{{STRUCTURE_2gpl|  PDB=2gpl  |  SCENE=  }}  


'''TMC-95 based biphenyl-ether macrocycles: specific proteasome inhibitors'''
===TMC-95 based biphenyl-ether macrocycles: specific proteasome inhibitors===




==Overview==
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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.
The line below this paragraph, {{ABSTRACT_PUBMED_16793518}}, adds the Publication Abstract to the page
(as it appears on PubMed at http://www.pubmed.gov), where 16793518 is the PubMed ID number.
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{{ABSTRACT_PUBMED_16793518}}


==About this Structure==
==About this Structure==
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[[Category: Ntn-hydrolase]]
[[Category: Ntn-hydrolase]]
[[Category: Proteasomal subunit fold represents an antiparallel beta-sheet flanked by helice]]
[[Category: Proteasomal subunit fold represents an antiparallel beta-sheet flanked by helice]]
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