Schematic representation of plasmin inhibition by α2AP. α2AP inhibits plasmin by forming a 1:1 stable complex with plasmin. The reaction proceeds via a 2-step mechanism. Initially, in a reversible second-order reaction (small upper left box), the C-terminal end of α2AP, which contains 6 lysine residues, binds noncovalently to the LBSs present in the kringle domains of plasmin. On the basis of structural studies, it has been suggested that the α2AP C-terminal lysines interact with the kringle domains of plasmin in a cooperative zipper-like manner, although it has not yet been determined which lysines bind to which LBS.⁴⁶  Kringle 3, the only non-lysine binding plasmin kringle, possibly adds to the binding between plasmin and α2AP by interacting with the highly electronegative sulfotyrosine (Tyr457-SO₄) present in the α2AP C terminus.²³  In the second step (large rightmost box), which is an irreversible first-order reaction, the arginine residue at position 376 of α2AP in the reactive center loop forms a covalent bond with the active site serine residue at position 741 of plasmin. This results in formation of the PAP complex accompanied by complete loss of plasmin activity. The scribble between the A-chain and B-chain of plasmin represents 2 disulfide bridges.