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Title:Insights Into the Dynamic Structure and Inhibitory Mechanism of Plasminogen Activator Inhibitor Type 1
Author(s):Li, Shih-Hon
Doctoral Committee Chair(s):Schwartz, Bradford S.
Department / Program:Biochemistry
Discipline:Biochemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):Chemistry, Biochemistry
Abstract:The aim of this study was to delineate the biochemical differences between wild-type PAI-1 (wtPAI-1) and 14-1B and to infer structural and functional details about the naturally occurring inhibitor using the structural model of the stable variant as a starting point. Using conformationally-sensitive ligands, we found that the RCL of PAI-1 exhibited more partial insertion into the beta-sheet A and that beta-sheet A was more accessible to the mobile RCL than was evident from the crystal structure of 14-1B. These properties suggested that PAI-1 be grouped in a novel sub-class of serpins exhibiting partially-inserted RCLs and allowed further study of its structure-function relationships in a new light. The accessibility of beta-sheet A to the RCL in 14-1B is limited by mutations in the hF/s3A loop sub-domain, diminishing partial insertion of the RCL and presumably reducing the rate of full loop insertion during protease inhibition. We provide evidence strongly suggesting that these hindrances to RCL flexibility and mobility affect the mechanism by which PAI-1 inactivates t-PA at several steps, perturbing the initial non-covalent binding, slowing the formation of the acyl-enzyme complex, and compromising the stabilization of the acyl-enzyme intermediate. The work provides a more comprehensive structural model for the active conformation of PAI-1 and illuminates a new role for the hF/s3A loop sub-domain in the inhibitory mechanism of serpins.
Issue Date:2008
Type:Text
Language:English
Description:147 p.
Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2008.
URI:http://hdl.handle.net/2142/84857
Other Identifier(s):(MiAaPQ)AAI3337878
Date Available in IDEALS:2015-09-25
Date Deposited:2008


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