PDBsum entry: 1deu

Hydrolase

PDB id: 1deu

Contents

Protein chains

275 a.a. *

261 a.a. *

Waters ×428

* Residue conservation analysis

PDB id:

1deu

Name:

Hydrolase

Title:

Crystal structure of human procathepsin x: a cysteine protea the proregion covalently linked to the active site cysteine

Structure:

Procathepsin x. Chain: a, b

Source:

Homo sapiens. Human. Organism_taxid: 9606

Biol. unit:

Dimer (from PQS)

Resolution:

1.70Å R-factor: 0.204 R-free: 0.215

Authors:

J.Sivaraman,D.K.Nagler,R.Zhang,R.Menard,M.Cygler

Key ref:

J.Sivaraman et al. (2000). Crystal structure of human procathepsin X: a cysteine protease with the proregion covalently linked to the active site cysteine. J Mol Biol, 295, 939-951. PubMed id: 10656802 DOI: 10.1006/jmbi.1999.3410

Date:

15-Nov-99 Release date: 18-Feb-00

Protein chain

Q9UBR2  (CATZ_HUMAN) -  Cathepsin Z

Seq: 303 a.a.

Struc: 275 a.a.*

Protein chain

Q9UBR2  (CATZ_HUMAN) -  Cathepsin Z

Seq: 303 a.a.

Struc: 261 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: Chains A, B: E.C.3.4.18.1 - Cathepsin X.
• Reaction: Liberation of C-terminal amino acid residue, with broad specificity, but lacks action on C-terminal proline.

 Gene Ontology (GO) functional annotation 

• Cellular component: extracellular space (3 terms)
• Biological process: proteolysis (2 terms)
• Biochemical function: hydrolase activity (4 terms)

DOI no: 10.1006/jmbi.1999.3410

J Mol Biol 295:939-951 (2000)

PubMed id: 10656802

Crystal structure of human procathepsin X: a cysteine protease with the proregion covalently linked to the active site cysteine.

J.Sivaraman, D.K.Nägler, R.Zhang, R.Ménard, M.Cygler.

ABSTRACT

Human cathepsin X is one of many proteins discovered in recent years through the mining of sequence databases. Its sequence shows clear homology to cysteine proteases from the papain family, containing the characteristic residue patterns, including the active site. However, the proregion of cathepsin X is only 38 residues long, the shortest among papain-like enzymes, and the cathepsin X sequence has an atypical insertion in the regions proximal to the active site. This protein was recently expressed and partially characterized biochemically. Unlike most other cysteine proteases from the papain family, procathepsin X is incapable of autoprocessing in vitro but can be processed under reducing conditions by exogenous cathepsin L. Atypically, the mature enzyme is primarily a carboxypeptidase and has extremely poor endopeptidase activity. We have determined the three-dimensional structure of the procathepsin X at 1.7 A resolution. The overall structure of the mature enzyme is characteristic for enzymes of the papain superfamily, but contains several novel features. Most interestingly, the short proregion binds to the enzyme with the aid of a covalent bond between the cysteine residue in the proregion (Cys10p) and the active site cysteine residue (Cys31). This is the first example of a zymogen in which the inhibition of enzyme's proteolytic activity by the proregion is achieved through a reversible covalent modification of the active site nucleophile. Such mode of binding requires less contact area between the proregion and the enzyme than observed in other procathepsins, and no auxiliary binding site on the enzyme surface is used. A three-residue insertion in a highly conserved region, just prior to the active site cysteine residue, confers a significantly different shape on the S' subsites, compared to other proteases from papain family. The 3D structure provides an explanation for the rather unusual carboxypeptidase activity of this enzyme and confirms the predictions based on homology modeling. Another long insertion in the cathepsin X amino acid sequence forms a beta-hairpin pointing away from the active site. This insertion, thought to be an equivalent of cathepsin B occluding loop, is located on the side of the protein, distant from the substrate binding site.

Selected figure(s)

Figure 1.
Figure 1. Schematic view of procathepsin X displaying the secondary structural elements. The proregion is colored light brown, the enzyme is green with the 25 C-terminal residues dark green, the mini-loop is magenta, the large insertion is blue and the disulfides are red (conserved) and yellow (unique). The active site Cys31 and His180 are colored blue and shown in full. The Figure was prepared with MOLSCRIPT [Kraulis 1991].

Figure 4.
Figure 4. Contacts between the proregion and the cathepsin X outside the substrate binding site. The proregion is shown with a thick line, hydrogen bonds are shown with broken lines.

The above figures are reprinted by permission from Elsevier: J Mol Biol (2000, 295, 939-951) copyright 2000.

Figures were selected by an automated process.