Crystal structure of neuropsin, a hippocampal protease involved in kindling epileptogenesis

Neuropsin is a novel serine protease, the expression of which is highly loc alized in the limbic areas of the mouse brain and which is suggested to be involved in kindling epileptogenesis and hippocampal plasticity, The 2.1-An gstrom resolution crystal structure of neuropsin provides the first three-d imensional view of one of the serine proteases highly expressed in the nerv ous system, and reveals a serine protease fold that exhibits chimeric featu res between trypsin and nerve growth factor-gamma (NGF gamma), a member of the kallikrein family. Neuropsin possesses an N-glycosylated "kallikrein lo op" but forms six disulfide bonds corresponding to those of trypsin, The or dered kallikrein loop projects proline toward the active site tee restrict smaller residues or proline at the P2 position of substrates. Loop F, which participates in forming the S3/S4 sites, is similar to trypsin rather than NGF gamma. The unique conformations of loops G and H form an S1 pocket spe cific for both arginine and lysine, These characteristic loop structures fo rming the substrate-binding site suggest the novel substrate specificity of neuropsin and give a clue to the design of its specific inhibitors.