PDBsum entry 1h4w

Hydrolase

PDB id: 1h4w

Contents

Protein chain

224 a.a. *

Ligands

BEN

Metals

_CA

Waters ×125

* Residue conservation analysis

PDB id:

1h4w

Name:

Hydrolase

Title:

Structure of human trypsin iv (brain trypsin)

Structure:

Trypsin iva. Chain: a. Engineered: yes. Other_details: benzamidine

Source:

Homo sapiens. Human. Organism_taxid: 9606. Variant: a form. Organ: brain. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

1.70Å R-factor: 0.188 R-free: 0.203

Authors:

G.Katona,G.I.Berglund,J.Hajdu,L.Graf,L.Szilagyi

Key ref:

G.Katona et al. (2002). Crystal structure reveals basis for the inhibitor resistance of human brain trypsin. J Mol Biol, 315, 1209-1218. PubMed id: 11827488 DOI: 10.1006/jmbi.2001.5305

Date:

15-May-01 Release date: 11-Feb-02

Protein chain

P35030  (TRY3_HUMAN) -  Trypsin-3 from Homo sapiens

Seq: 304 a.a.

Struc: 224 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.4.21.4 - trypsin.
• Reaction: Preferential cleavage: Arg-|-Xaa, Lys-|-Xaa.

DOI no: 10.1006/jmbi.2001.5305

J Mol Biol 315:1209-1218 (2002)

PubMed id: 11827488

Crystal structure reveals basis for the inhibitor resistance of human brain trypsin.

G.Katona, G.I.Berglund, J.Hajdu, L.Gráf, L.Szilágyi.

ABSTRACT

Severe neurodegradative brain diseases, like Alzheimer, are tightly linked with proteolytic activity in the human brain. Proteinases expressed in the brain, such as human trypsin IV, are likely to be involved in the pathomechanism of these diseases. The observation of amyloid formed in the brain of transgenic mice expressing human trypsin IV supports this hypothesis. Human trypsin IV is also resistant towards all studied naturally occurring polypeptide inhibitors. It has been postulated that the substitution of Gly193 to arginine is responsible for this inhibitor resistance. Here we report the X-ray structure of human trypsin IV in complex with the inhibitor benzamidine at 1.7 A resolution. The overall fold of human trypsin IV is similar to human trypsin I, with a root-mean square deviation of only 0.5 A for all C(alpha) positions. The crystal structure reveals the orientation of the side-chain of Arg193, which occupies an extended conformation and fills the S2' subsite. An analysis of surface electrostatic potentials shows an unusually strong clustering of positive charges around the primary specificity pocket, to which the side-chain of Arg193 also contributes. These unique features of the crystal structure provide a structural basis for the enhanced inhibitor resistance, and enhanced substrate restriction, of human trypsin IV.

Selected figure(s)

Figure 4.
Figure 4. Electrostatic potential mapped onto the molecular surface of (a) human trypsin IV, (b) human trypsin I, (c) rat anionic trypsin and (d) bovine cationic trypsin. The contouring level of electrostatic potential is -18 kT/e (red) and 18 kT/e (blue). The orientation of the molecules is the same as in Figure 1(a).

Figure 5.
Figure 5. (a) View of the N-terminal loop of human trypsin IV. The SigmaA weighted 2mF[o] - DF[c] electron density map is contoured at 1s level. (b) Structural comparison of the N-terminal loops in human trypsin IV (black), human trypsin I (green), rat trypsin (cyan), bovine trypsin (magenta). Two alternative conformations are shown for Leu27.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2002, 315, 1209-1218) copyright 2002.

Figures were selected by an automated process.