Complexation of the tissue plasminogen activator protease with benzamidine-type inhibitors: interference by the kringle 2 module

Biochemistry
C K HuM Llinás

Abstract

Well-resolved high-field 1H NMR signals between -0.1 and -0.7 ppm afford convenient probes to monitor the conformational state of the tissue plasminogen activator (tPA) protease, modulated by covalent inhibitor binding or activation cleavage [Hu, C.-K., Kohnert, U., Wilhelm, O., Fischer, S., & Llinas, M. (1994) Biochemistry 33, 11760-11766]. We have investigated recombinant BM 06.022 (a domain-deletion variant mutant from Escherichia coli comprising the kringle 2 and protease modules) and protease constructs of tPA in both single-chain (sc) and two-chain (tc) forms. The two proteins were studied when confronted with the noncovalent (i.e., reversible) active site inhibitors benzamidine and a series of bisbenzamidine derivatives: 2,5-bis(4-amidinobenzylidene)cyclopentanone, 2,6-bis(4-amidinobenzylidene)cyclohexanone, 2,7-bis(4-amidinobenzylidene)cycloheptanone, and 2,8-bis(4-amidino- benzylidene)cyclooctanone. At pH* 4.6, the 1H NMR spectrum is sensitive to complexation of the protease module with the various effectors. The amplitude of the inhibitor-shifted resonances is more pronounced for the tc-protease than for the sc-protease, suggesting that access of inhibitors to the protease catalytic site is facilitated upon conversion...Continue Reading

References

Jan 1, 1987·European Biophysics Journal : EBJ·A De MarcoM Llinás

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Citations

Sep 23, 2003·Journal of Controlled Release : Official Journal of the Controlled Release Society·Nathalie PoulainEvelyne Nakache
Sep 22, 2006·Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis·Fania SzlamKenichi A Tanaka
Feb 27, 2009·Acta Anaesthesiologica Scandinavica·H-Y SunK A Tanaka
Jul 29, 2010·Protein Science : a Publication of the Protein Society·Alexander TischerChristian Lange
Jun 17, 2021·The Protein Journal·Manuel Llinás

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