Chapter 5 - Regulation of Proteases by Protein Inhibitors of the Serpin... http://www.sciencedirect.

com/science/article/pii/B9780123855046000051

Register

Login

Home

Publications

Search

My settings

My alerts
More options...

Help
Search ScienceDirect
http://dx.doi.org/10.1016 /B978-0-12-385504-6.00005-1 Get rights and content

Export citation

Show thumbnails in outline

Keywords I. Overview of the Serpin Superfamily A. Discovery of Serpins Table I B. Serpin Classification C. Biology of Human Serpins D. Structural Features of Serpins

Progress in Molecular Biology and Translational Science

Volume 99, 2011, Pages 185240 Proteases in Health and Disease

Bibliographic information Citing and recommended articles

Chapter 5 Regulation of Proteases by Protein Inhibitors of the Serpin Superfamily

Steven T. Olson

Recommended articles Molecular mechanisms of antithrombinhe

2010, Biochimie Show more information

, Peter G.W. Gettins

Center for Molecular Biology of Oral Diseases, University of Illinois at Chicago, Chicago, Illinois, USA The Center for Structural Biology, University of Illinois at Chicago, Chicago, Illinois, USA Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois, USA

Shape-shifting serpins advantages of a m

2006, Trends in Biochemical Sciences Show more information

Choose an option to locate/access this article:

Aprotinin and similar protease inhibitors as

2011, Antiviral Research Show more information

E. Serpins and Conformational Disease

The serpins comprise an ancient superfamily of proteins, found abundantly in eukaryotes and even in some bacteria and archea, that have evolved to regulate proteases of both serine and cysteine mechanistic classes. Unlike the thermodynamically determined lock-and-key type inhibitors, such as those of the Kunitz and Kazal families, serpins use conformational change and consequent kinetic trapping of an enzyme intermediate to effect inhibition. By combining interactions of both an exposed reactive center loop and exosites outside this loop with the active site and complementary exosites on the target protease, serpins can achieve remarkable specificity. Together with the frequent use of regulatory cofactors, this permits a sophisticated time- and location-dependent mode of protease regulation. An understanding of the structure and function of serpins has suggested that they may provide novel scaffolds for engineering protease inhibitors of desired specificity for therapeutic use.

View more articles

Related reference work articles FIBRINOLYSIS | Overview

2006, Encyclopedia of Respiratory Medicine Show more information

COAGULATION CASCADE | iuPA, tPA, uP

2006, Encyclopedia of Respiratory Medicine Show more information

Keywords
Serpin; Protease; Heparin; Allostery; Exosites; Protease inhibitor; Protein engineering Figures and tables from this article: II. Mechanism of Action A. The Serpin Suicide Substrate Inhibition Mechanism Applications and tools Workspace

Fig. 1. Native serpin structure. Front and back stereo views of the structure of the serpin, PI in its native state (pdb 1QLP), in ribbon
1

representation. The ~ 350 amino acid core domain consists of three beta sheets, nine alpha helices (AJ), and a prominent

B. The Michaelis Complex

reactive center loop (RCL) that protrudes from the top end of the molecule. Beta sheets are red (sheet A), blue (sheet B), and green (sheet C) and helices are yellow. Reprinted with permission from Ref. 1. Copyright 2002 American Chemical Society. Figure options

Table II

Fig. 2.

C. Covalent Complex

Conserved residues in serpins. Shown is a stereo view of the RCL-cleaved PI structure in backbone representation (gray,
1

pdb 7API) depicting the location of the 51 highly conserved residues in > 70% of serpins in ball-and-stick representation (blue) that were identified by Irving et al. Most of the conserved residues are part of the hydrophobic core. Reprinted with permission from Ref. 1. Copyright 2002 American Chemical Society. Figure options
9

D. Cleaved Serpin E. Stability of the Covalent Complex F. Energetics of Complex Formation G. Clearance of Complexes III. Rates of Reaction, Specificity, and Regulation A. Simple RCL Interactions B. Exosite Interactions in Binary Complexes

Fig. 3. Conformational states of serpins. Comparison of X-ray structures of the metastable native serpin conformation (A; PI, pdb
1

1QLP) and the more stable RCL-cleaved (B; PI, pdb 7API), and latent (C; PAI-1, pdb 1C5G) conformations. Also shown is
1

the unusual -conformation of an -antichymotrypsin L55P variant with a mutation in the shutter region (D; pdb 1QMN). All
1

structures are shown in ribbon representation with the RCL colored blue, the A -sheet red, and the remainder of the structure in gray. Reprinted with permission from Ref. 1. Copyright 2002 American Chemical Society.

1 de 1

12/11/2013 14:40