Crystal Structure of the Michaelis Complex between Tissue-type Plasminogen Activator and Plasminogen Activators Inhibitor-1.

The Journal of Biological Chemistry
Lihu GongMingdong Huang

Abstract

Thrombosis is a leading cause of death worldwide. Recombinant tissue-type plasminogen activator (tPA) is the Food and Drug Administration-approved thrombolytic drug. tPA is rapidly inactivated by endogenous plasminogen activator inhibitor-1 (PAI-1). Engineering on tPA to reduce its inhibition by PAI-1 without compromising its thrombolytic effect is a continuous effort. Precise details, with atomic resolution, of the molecular interactions between tPA and PAI-1 remain unknown despite previous extensive studies. Here, we report the crystal structure of the tPA·PAI-1 Michaelis complex, which shows significant differences from the structure of its urokinase-type plasminogen activator analogue, the uPA·PAI-1 Michaelis complex. The PAI-1 reactive center loop adopts a unique kinked conformation. The structure provides detailed interactions between tPA 37- and 60-loops with PAI-1. On the tPA side, the S2 and S1β pockets open up to accommodate PAI-1. This study provides structural basis to understand the specificity of PAI-1 and to design newer generation of thrombolytic agents with reduced PAI-1 inactivation.

References

May 1, 1990·Proceedings of the National Academy of Sciences of the United States of America·E L MadisonR S Bassel-Duby
Jun 29, 1989·Nature·E L MadisonJ F Sambrook
Apr 26, 1994·Proceedings of the National Academy of Sciences of the United States of America·B A KeytJ Ogez
Nov 1, 1995·Journal of Biomolecular NMR·F DelaglioA Bax
Apr 7, 2000·Protein Science : a Publication of the Protein Society·A VindigniE Di Cera
Jun 15, 2000·The New England Journal of Medicine·H P Kohler, P J Grant
Oct 31, 2001·Nature Structural Biology·S YeE J Goldsmith
Nov 22, 2002·The Journal of Biological Chemistry·Katrin SichlerHans Brandstetter
Nov 5, 2003·The Journal of Biological Chemistry·Catherine A IbarraJoseph D Shore
May 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Aug 18, 2004·Nature Structural & Molecular Biology·Wei LiJames A Huntington
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Nov 9, 2005·Vascular Pharmacology·Dev B BaruahS S Kadam
Aug 8, 2007·Journal of Molecular Biology·Evgeny Krissinel, Kim Henrick
Jun 13, 2008·Nature Reviews. Cancer·David R CroucherMarie Ranson
Mar 11, 2009·Frontiers in Bioscience (Landmark Edition)·Daniel Miotto DupontPeter Andre Andreasen
Jan 19, 2010·Proceedings of the National Academy of Sciences of the United States of America·Daniel J D JohnsonJames A Huntington
Jan 5, 2011·The Journal of Biological Chemistry·Zhonghui LinMingdong Huang
Mar 10, 2011·The Annals of Pharmacotherapy·Molly A Hatcher, Jessica A Starr
May 1, 2012·Journal of Thrombosis and Haemostasis : JTH·Y XueK Olsson
Oct 15, 2014·Thrombosis Research·UNKNOWN ISTH Steering Committee for World Thrombosis Day
Oct 15, 2014·Proceedings of the National Academy of Sciences of the United States of America·Giorgia CazzolliPatrick L Wintrode
Jan 1, 1997·Methods in Enzymology·Zbyszek Otwinowski, Wladek Minor

❮ Previous
Next ❯

Citations

Jan 5, 2017·Nucleic Acid Therapeutics·Nils BjerregaardPeter A Andreasen
May 20, 2017·Zhurnal voprosy neĭrokhirurgii imeni N. N. Burdenko·O I KitYu A Pogorelova
Feb 5, 2019·Expert Opinion on Drug Safety·Katleen Wyatt ChesterGeorge M Dillon
Jun 18, 2019·Acta Crystallographica. Section D, Structural Biology·Monika PathakJonas Emsley
Mar 10, 2018·Blood Advances·Alexey DementievJames R Partridge
Jan 19, 2019·BMC Evolutionary Biology·Andrés Chana-MuñozFrank Panitz
Mar 9, 2019·Scientific Reports·Emilia M MarijanovicAshley M Buckle
Aug 23, 2020·International Journal of Molecular Sciences·Machteld SillenPaul J Declerck
Apr 11, 2018·PeerJ·Jialing BaoZeyang Zhou
Mar 11, 2020·Experimental & Molecular Medicine·Haili LinPeng Xu
Jul 31, 2019·Computational and Structural Biotechnology Journal·Jan MicanJiri Damborsky
Jan 9, 2021·Frontiers in Cardiovascular Medicine·Machteld Sillen, Paul J Declerck
Feb 6, 2021·International Journal of Molecular Sciences·Machteld SillenPaul J Declerck
Jun 24, 2021·Journal of Thrombosis and Thrombolysis·Keaton S SmetanaShahid M Nimjee
Nov 17, 2021·British Journal of Haematology·Shanli ChenMingdong Huang

❮ Previous
Next ❯

Related Concepts

Related Feeds

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.

© 2021 Meta ULC. All rights reserved