Plasma kallikrein structure reveals apple domain disc rotated conformation compared to factor XI.

Journal of Thrombosis and Haemostasis : JTH
Chan LiJ Emsley

Abstract

Essentials Zymogen PK is activated to PKa and cleaves substrates kininogen and FXII contributing to bradykinin generation. Monomeric PKa and dimeric homologue FXI utilize the N-terminal apple domains to recruit substrates. A high-resolution 1.3 Å structure of full-length PKa reveals an active conformation of the protease and apple domains. The PKa protease and four-apple domain disc organization is 180° rotated compared to FXI. SUMMARY: Background Plasma prekallikrein (PK) and factor XI (FXI) are apple domain-containing serine proteases that when activated to PKa and FXIa cleave substrates kininogen, factor XII, and factor IX, respectively, directing plasma coagulation, bradykinin release, inflammation, and thrombosis pathways. Objective To investigate the three-dimensional structure of full-length PKa and perform a comparison with FXI. Methods A series of recombinant full-length PKa and FXI constructs and variants were developed and the crystal structures determined. Results and conclusions A 1.3 Å structure of full-length PKa reveals the protease domain positioned above a disc-shaped assemblage of four apple domains in an active conformation. A comparison with the homologous FXI structure reveals the intramolecular disulfide ...Continue Reading

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Citations

Dec 5, 2019·Journal of Thrombosis and Haemostasis : JTH·David Gailani, Jonas Emsley
Dec 5, 2019·Blood·Ivan IvanovDavid Gailani
Feb 23, 2020·Blood·Jonas Emsley
Oct 28, 2020·Journal of Thrombosis and Haemostasis : JTH·Aleksandr ShamanaevDavid Gailani
Dec 23, 2020·Blood Advances·Michał B PonczekDavid Gailani
Feb 18, 2020·European Journal of Medicinal Chemistry·Zhouling XieChenzhong Liao
May 25, 2021·Research and Practice in Thrombosis and Haemostasis·Anna C MavromanoliStavros V Konstantinides

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Methods Mentioned

BETA
glycosylation
transfection
gel filtration

Software Mentioned

Dynamx
CCP4
Protein Lynx Global
STRIDE
XDS
SWISSMODEL
PHASER

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