PDBsum entry 1npm

Serine proteinase

PDB id: 1npm

Contents

Protein chains

223 a.a. *

Ligands

NAG ×2

Waters ×194

* Residue conservation analysis

PDB id:

1npm

Name:

Serine proteinase

Title:

Neuropsin, a serine protease expressed in the limbic system of mouse brain

Structure:

Neuropsin. Chain: a, b. Engineered: yes

Source:

Mus musculus. House mouse. Organism_taxid: 10090. Cell_line: high5. Organ: hippocampus. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: high5.

Resolution:

2.10Å R-factor: 0.186 R-free: 0.227

Authors:

T.Kishi,M.Kato,T.Shimizu,K.Kato,K.Matsumoto,S.Yoshida,S.Shiosaka, T.Hakoshima

Key ref:

T.Kishi et al. (1999). Crystal structure of neuropsin, a hippocampal protease involved in kindling epileptogenesis. J Biol Chem, 274, 4220-4224. PubMed id: 9933620 DOI: 10.1074/jbc.274.7.4220

Date:

07-Jan-98 Release date: 23-Mar-99

Protein chains

Q61955  (KLK8_MOUSE) -  Kallikrein-8 from Mus musculus

Seq: 260 a.a.

Struc: 223 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.21.118 - kallikrein 8.

DOI no: 10.1074/jbc.274.7.4220

J Biol Chem 274:4220-4224 (1999)

PubMed id: 9933620

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

T.Kishi, M.Kato, T.Shimizu, K.Kato, K.Matsumoto, S.Yoshida, S.Shiosaka, T.Hakoshima.

ABSTRACT

Neuropsin is a novel serine protease, the expression of which is highly localized in the limbic areas of the mouse brain and which is suggested to be involved in kindling epileptogenesis and hippocampal plasticity. The 2.1-A resolution crystal structure of neuropsin provides the first three-dimensional view of one of the serine proteases highly expressed in the nervous system, and reveals a serine protease fold that exhibits chimeric features between trypsin and nerve growth factor-gamma (NGFgamma), a member of the kallikrein family. Neuropsin possesses an N-glycosylated "kallikrein loop" but forms six disulfide bonds corresponding to those of trypsin. The ordered kallikrein loop projects proline toward the active site to 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 NGFgamma. The unique conformations of loops G and H form an S1 pocket specific for both arginine and lysine. These characteristic loop structures forming the substrate-binding site suggest the novel substrate specificity of neuropsin and give a clue to the design of its specific inhibitors.

Selected figure(s)

Figure 1.
Fig. 1. Overall structure of neuropsin. a, ribbon representation of neuropsin. Seven-stranded -sheets (the top and bottom halves) are sandwiched with the catalytic triad at the cleft of the -sandwich. The surface loops (A-H) forming the substrate-binding site are colored with labels. Six disulfide bonds are shown by bridges in white, and the disulfide bond (SS3), which is conserved in trypsin but not in kallikrein, was labeled. Loop D is the kallikrein loop that has an N-glycosylated Asn95 with one visible GlcNAc residue. The side chains of the catalytic triad, Asp189 at the S1-specific pocket, Lys175 at the S3/4 site, Glu149 and Asp218 at the rim of the S1 pocket, and Leu40 and Ile^41 at the S1' site, are also shown with stick representations with one-letter amino acid labels. b, molecular surfaces of neuropsin viewed from nearly the same direction of panel a. Surface electrostatic potentials calculated and rendered using GRASP (negative potentials are in red and positive in blue). The S1-S4 and S1' sites and characteristic surface residues are labeled.

Figure 4.
Fig. 4. Comparison of the surface loops forming the S2 site between neuropsin (colored) and -thrombin (gray). The C[ ]-carbon atom tracings of loops of neuropsin, colored as in Fig. 1a, are superimposed on -thrombin complexed with D-Phe-Pro-Arg-chloromethylketone (green). The van der Waals surfaces of the inhibitor peptide and P95D are shown with dot-surface representations. Labels are as in Fig. 3.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (1999, 274, 4220-4224) copyright 1999.

Figures were selected by an automated process.