PDBsum entry: 1icf

Hydrolase

PDB id: 1icf

Contents

Protein chains

175 a.a. *

42 a.a. *

65 a.a. *

Ligands

NAG ×2

Waters ×668

* Residue conservation analysis

PDB id:

1icf

Name:

Hydrolase

Title:

Crystal structure of mhc class ii associated p41 ii fragment complex with cathepsin l

Structure:

Protein (cathepsin l: heavy chain). Chain: a, c. Protein (cathepsin l: light chain). Chain: b, d. Protein (invariant chain). Chain: i, j. Fragment: thyroglobulin type-1 domain. Synonym: ii fragment, cd74 fragment

Source:

Homo sapiens. Human. Organism_taxid: 9606. Organ: kidney. Organ: kidney

Biol. unit:

Trimer (from PQS)

Resolution:

2.00Å R-factor: 0.182 R-free: 0.213

Authors:

G.Guncar,G.Pungercic,I.Klemencic,V.Turk,D.Turk

Key ref:

G.Guncar et al. (1999). Crystal structure of MHC class II-associated p41 Ii fragment bound to cathepsin L reveals the structural basis for differentiation between cathepsins L and S. Embo J, 18, 793-803. PubMed id: 10022822 DOI: 10.1093/emboj/18.4.793

Date:

07-Jan-99 Release date: 12-Jan-00

Protein chains

P07711  (CATL1_HUMAN) -  Cathepsin L1

Seq: 333 a.a.

Struc: 175 a.a.

Protein chains

P07711  (CATL1_HUMAN) -  Cathepsin L1

Seq: 333 a.a.

Struc: 42 a.a.

Protein chains

P04233  (HG2A_HUMAN) -  HLA class II histocompatibility antigen gamma chain

Seq: 296 a.a.

Struc: 65 a.a.

Enzyme reactions

• Enzyme class: Chains A, B, C, D: E.C.3.4.22.15 - Cathepsin L.
• Reaction: Specificity close to that of papain. As compared to cathepsin B, cathepsin L exhibits higher activity towards protein substrates, but has little activity on Z-Arg-Arg-NHMec, and no peptidyl-dipeptidase activity.

 Gene Ontology (GO) functional annotation 

• Biological process: proteolysis (1 term)
• Biochemical function: cysteine-type peptidase activity (2 terms)

DOI no: 10.1093/emboj/18.4.793

Embo J 18:793-803 (1999)

PubMed id: 10022822

Crystal structure of MHC class II-associated p41 Ii fragment bound to cathepsin L reveals the structural basis for differentiation between cathepsins L and S.

G.Guncar, G.Pungercic, I.Klemencic, V.Turk, D.Turk.

ABSTRACT

The lysosomal cysteine proteases cathepsins S and L play crucial roles in the degradation of the invariant chain during maturation of MHC class II molecules and antigen processing. The p41 form of the invariant chain includes a fragment which specifically inhibits cathepsin L but not S. The crystal structure of the p41 fragment, a homologue of the thyroglobulin type-1 domains, has been determined at 2.0 A resolution in complex with cathepsin L. The structure of the p41 fragment demonstrates a novel fold, consisting of two subdomains, each stabilized by disulfide bridges. The first subdomain is an alpha-helix-beta-strand arrangement, whereas the second subdomain has a predominantly beta-strand arrangement. The wedge shape and three-loop arrangement of the p41 fragment bound to the active site cleft of cathepsin L are reminiscent of the inhibitory edge of cystatins, thus demonstrating the first example of convergent evolution observed in cysteine protease inhibitors. However, the different fold of the p41 fragment results in additional contacts with the top of the R-domain of the enzymes, which defines the specificity-determining S2 and S1' substrate-binding sites. This enables inhibitors based on the thyroglobulin type-1 domain fold, in contrast to the rather non-selective cystatins, to exhibit specificity for their target enzymes.

Selected figure(s)

Figure 2.
Figure 2 Schematic representation of the p41 fragment fold and its contacts with cathepsin L. p41 fragment residues are represented as circles, and interacting cathepsin L residues as squares. Dark grey shaded circles represent the C–CWC–C building element. Disulfide bridges are represented as dashed winding lines, hydrogen bonds and electrostatic interactions as dashed lines, and hydrophobic interactions as thin dotted lines. The Asn240F residue was observed in the electron density map to be glycosylated and is represented by a triangle.

Figure 7.
Figure 7 Structural role of the CWC sequence motif. The CWC sequence forms the core of the interface between the subdomains of the p41 fragment (thick lines) and of the superimposed fibrin-binding finger domain of tissue-type plasminogen activator (thin lines) (Downing et al., 1992). The figure was prepared with the program MAIN (Turk, 1992).

The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: Embo J (1999, 18, 793-803) copyright 1999.

Figures were selected by an automated process.