4aqh
Plasminogen activator inhibitor type-1 in complex with the inhibitor AZ3976
Structural highlights
DiseasePAI1_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. FunctionPAI1_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 PubMedA novel class of small molecule inhibitors for plasminogen activator inhibitor type 1 (PAI-1), represented by AZ3976, was identified in a high throughput screening campaign. AZ3976 displayed an IC(50) value of 26 mum in an enzymatic chromogenic assay. In a plasma clot lysis assay, the compound was active with an IC(50) of 16 mum. Surprisingly, AZ3976 did not bind to active PAI-1 but bound to latent PAI-1 with a K(D) of 0.29 mum at 35 degrees C and a binding stoichiometry of 0.94, as measured by isothermal calorimetry. Reversible binding was confirmed by surface plasmon resonance direct binding experiments. The x-ray structure of AZ3976 in complex with latent PAI-1 was determined at 2.4 A resolution. The inhibitor was bound in the flexible joint region with the entrance to the cavity located between alpha-helix D and beta-strand 2A. A set of surface plasmon resonance experiments revealed that AZ3976 inhibited PAI-1 by enhancing the latency transition of active PAI-1. Because AZ3976 only had measurable affinity for latent PAI-1, we propose that its mechanism of inhibition is based on binding to a small fraction in equilibrium with active PAI-1, a latent-like prelatent form, from which latent PAI-1 is then generated more rapidly. This mode of action, with induced accelerated latency transition of active PAI-1 may, together with supporting x-ray data, provide improved opportunities for small molecule drug design in the hunt for therapeutically useful PAI-1 inhibitors. Characterization of a small molecule inhibitor of plasminogen activator inhibitor type 1 that accelerates the transition into the latent conformation.,Fjellstrom O, Deinum J, Sjogren T, Johansson C, Geschwindner S, Nerme V, Legnehed A, McPheat J, Olsson K, Bodin C, Paunovic A, Gustafsson D J Biol Chem. 2013 Jan 11;288(2):873-85. doi: 10.1074/jbc.M112.371732. Epub 2012, Nov 15. PMID:23155046[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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