Structural highlights
Disease[PAI1_HUMAN] Defects in SERPINE1 are the cause of plasminogen activator inhibitor-1 deficiency (PAI-1D) [MIM:613329]. It is a hematologic disorder characterized by increased bleeding after trauma, injury, or surgery. Affected females have menorrhagia. The bleeding defect is due to increased fibrinolysis of fibrin blood clots due to deficiency of plasminogen activator inhibitor-1, which inhibits tissue and urinary activators of plasminogen.[1] Note=High concentrations of SERPINE1 seem to contribute to the development of venous but not arterial occlusions. Function[PAI1_HUMAN] Serine protease inhibitor. This inhibitor acts as 'bait' for tissue plasminogen activator, urokinase, protein C and matriptase-3/TMPRSS7. Its rapid interaction with PLAT may function as a major control point in the regulation of fibrinolysis.[2] Publication Abstract from PubMedBACKGROUND: Plasminogen activator inhibitor-1 (PAI-1), a key inhibitor of plasminogen activators (PAs) tissue-type PA (tPA) and urokinase-type PA (uPA) plays a crucial role in many (patho)physiological processes, e.g. cardiovascular disease, tissue fibrosis, as well as in many age-related pathologies. Therefore, much effort has been put into the development of small molecule or antibody-based PAI-1 inhibitors. OBJECTIVE: To elucidate the molecular mechanism of nanobody-induced PAI-1 inhibition. METHODS AND RESULTS: Here we present the first crystal structures of PAI-1 in complex with two neutralizing nanobodies (Nbs). These structures, together with biochemical and biophysical characterization, reveal that Nb VHH-2g-42 (Nb42) interferes with the initial PAI-1/PA complex formation, whereas VHH-2w-64 (Nb64) redirects the PAI-1/PA interaction to PAI-1 deactivation and regeneration of active PA. Furthermore, whereas vitronectin (Vn) does not have an impact on the inhibitory effect of Nb42, it strongly potentiates the inhibitory effect of Nb64, which may contribute to a strong inhibitory potential of Nb64 in vivo. CONCLUSIONS: These findings illuminate the molecular mechanisms of PAI-1 inhibition. Nb42 and Nb64 can be used as starting points to engineer further improved antibody-based PAI-1 inhibitors or guide the rational design of small molecule inhibitors to treat a wide range of PAI-1-related pathophysiological conditions. Molecular mechanism of two nanobodies that inhibit PAI-1 activity reveals a modulation at distinct stages of the PAI-1/plasminogen activator interaction.,Sillen M, Weeks SD, Zhou X, Komissarov AA, Florova G, Idell S, Strelkov SV, Declerck PJ J Thromb Haemost. 2019 Dec 19. doi: 10.1111/jth.14716. PMID:31858714[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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