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Publication Abstract from PubMed

Plasminogen activator inhibitor-1 (PAI-1) is the main physiological inhibitor of tissue-type (tPA) and urokinase-type (uPA) plasminogen activators (PAs). Apart from being critically involved in fibrinolysis and wound healing, emerging evidence indicates that PAI-1 plays an important role in many diseases, including cardiovascular disease, tissue fibrosis, and cancer. Targeting PAI-1 is therefore a promising therapeutic strategy in PAI-1 related pathologies. Despite ongoing efforts no PAI-1 inhibitors were approved to date for therapeutic use in humans. A better understanding of the molecular mechanisms of PAI-1 inhibition is therefore necessary to guide the rational design of PAI-1 modulators. Here, we present a 1.9 A crystal structure of PAI-1 in complex with an inhibitory nanobody VHH-s-a93 (Nb93). Structural analysis in combination with biochemical characterization reveals that Nb93 directly interferes with PAI-1/PA complex formation and stabilizes the active conformation of the PAI-1 molecule.

Structural Insights into the Mechanism of a Nanobody That Stabilizes PAI-1 and Modulates Its Activity.,Sillen M, Weeks SD, Strelkov SV, Declerck PJ Int J Mol Sci. 2020 Aug 15;21(16):5859. doi: 10.3390/ijms21165859. PMID:32824134^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.