Abstract:
:We present a common allosteric mechanism for control of inflammatory and apoptotic caspases. Highly specific thiol-containing inhibitors of the human inflammatory caspase-1 were identified by using disulfide trapping, a method for site-directed small-molecule discovery. These compounds became trapped by forming a disulfide bond with a cysteine residue in the cavity at the dimer interface approximately 15 A away from the active site. Mutational and structural analysis uncovered a linear circuit of functional residues that runs from one active site through the allosteric cavity and into the second active site. Kinetic analysis revealed robust positive cooperativity not seen in other endopeptidases. Recently, disulfide trapping identified a similar small-molecule site and allosteric transition in the apoptotic caspase-7 that shares only a 23% sequence identity with caspase-1. Together, these studies show a general small-molecule-binding site for functionally reversing the zymogen activation of caspases and suggest a common regulatory site for the allosteric control of inflammation and apoptosis.
journal_name
Proc Natl Acad Sci U S Aauthors
Scheer JM,Romanowski MJ,Wells JAdoi
10.1073/pnas.0602571103subject
Has Abstractpub_date
2006-05-16 00:00:00pages
7595-600issue
20eissn
0027-8424issn
1091-6490pii
0602571103journal_volume
103pub_type
杂志文章abstract::Lampreys are one of the two surviving jawless vertebrate groups and one of a few vertebrate groups with the best exemplified metamorphosis during their life cycle, which consists of a long-lasting larval stage, a peculiar metamorphosis, and a relatively short adulthood with a markedly different anatomy. Although the f...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1415716111
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:2010-09-21 00:00:00