3pb1

Publication Abstract from PubMed

Plasminogen activator inhibitor-1 (PAI-1), together with its physiological target urokinase-type plasminogen activator (uPA), plays a pivotal role in fibrinolysis, cell migration, and tissue remodeling and is currently recognized as being among the most extensively validated biological prognostic factors in several cancer types. PAI-1 specifically and rapidly inhibits uPA and tissue-type PA (tPA). Despite extensive structural/functional studies on these two reactions, the underlying structural mechanism has remained unknown due to the technical difficulties of obtaining the relevant structures. Here, we report a strategy to generate a PAI-1.uPA(S195A) Michaelis complex and present its crystal structure at 2.3-A resolution. In this structure, the PAI-1 reactive center loop serves as a bait to attract uPA onto the top of the PAI-1 molecule. The P4-P3' residues of the reactive center loop interact extensively with the uPA catalytic site, accounting for about two-thirds of the total contact area. Besides the active site, almost all uPA exosite loops, including the 37-, 60-, 97-, 147-, and 217-loops, are involved in the interaction with PAI-1. The uPA 37-loop makes an extensive interaction with PAI-1 beta-sheet B, and the 147-loop directly contacts PAI-1 beta-sheet C. Both loops are important for initial Michaelis complex formation. This study lays down a foundation for understanding the specificity of PAI-1 for uPA and tPA and provides a structural basis for further functional studies.

Structural basis for recognition of urokinase-type plasminogen activator by plasminogen activator inhibitor-1.,Lin Z, Jiang L, Yuan C, Jensen JK, Zhang X, Luo Z, Furie BC, Furie B, Andreasen PA, Huang M J Biol Chem. 2011 Mar 4;286(9):7027-32. Epub 2011 Jan 3. PMID:21199867^[3]

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