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Thromb Haemost 2013; 110(03): 423-433
DOI: 10.1160/TH12-11-0840
Theme Issue Article
Schattauer GmbH

Structure of plasma and tissue kallikreins

Monika Pathak
1   Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, UK
,
Szu Shen Wong
1   Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, UK
,
Ingrid Dreveny
1   Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, UK
,
Jonas Emsley
1   Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham, UK
› Author Affiliations
Further Information

Publication History

Received: 19 November 2012

Accepted after major revision: 27 February 2013

Publication Date:
22 November 2017 (online)

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Summary

The kallikrein kinin system (KKS) consists of serine proteases involved in the production of peptides called kinins, principally bradykinin and Lys-bradykinin (kallidin). The KKS contributes to a variety of physiological processes including inflammation, blood pressure control and coagulation. Here we review the protein structural data available for these serine proteases and examine the molecular mechanisms of zymogen activation and substrate recognition focusing on plasma kallikrein (PK) and tissue kallikrein (KLK1) cleavage of kininogens. PK circulates as a zymogen bound to high-molecular-weight kininogen (HK). PK is activated by coagulation factor XIIa and then cleaves HK to generate bradykinin and factor XII to generate further XIIa. A structure has been described for the activated PK protease domain in complex with the inhibitor benzamidine. Kallikrein-related peptidases (KLKs) have a distinct domain structure and exist as a family of 15 genes which are differentially expressed in many tissues and the central nervous system. They cleave a wide variety of substrates including low-molecular-weight kininogen (LK) and matrix proteins. Crystal structures are available for KLK1, 3, 4, 5, 6 and 7 activated protease domains typically in complex with S1 pocket inhibitors. A substrate mimetic complex is described for KLK3 which provides insight into substrate recognition. A zymogen crystal structure determined for KLK6 reveals a closed S1 pocket and a novel mechanism of zymogen activation. Overall these structures have proved highly informative in understanding the molecular mechanisms of the KKS and provide templates to design inhibitors for treatment of a variety of diseases.

Keywords

Plasma kallikrein - tissue kallikrein - kininogen - zymogen activation - substrate recognition
 

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