PDBsum entry: 1mhw

Hydrolase/hydrolase inhibitor

PDB id: 1mhw

Contents

Protein chains

174 a.a. *

41 a.a. *

Ligands

BP4-CYS-DAR ×2

BP4-CYS-DAR-TYR-PEA ×2

Waters ×525

* Residue conservation analysis

PDB id:

1mhw

Name:

Hydrolase/hydrolase inhibitor

Title:

Design of non-covalent inhibitors of human cathepsin l. From residue proregion to optimized tripeptides

Structure:

Cathepsin l. Chain: a, b. Fragment: heavy chain (residues 114-288). Synonym: major excreted protein, mep. Engineered: yes. Cathepsin l. Chain: c, d. Fragment: light chain (residues 292-333). Synonym: major excreted protein, mep.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: pichia pastoris. Expression_system_taxid: 4922. Synthetic: yes

Biol. unit:

Tetramer (from PQS)

Resolution:

1.90Å R-factor: 0.185 R-free: 0.230

Authors:

S.Chowdhury,J.Sivaraman,J.Wang,G.Devanathan,P.Lachance,H.Qi, J.Lefebvre,Y.Konishi,M.Cygler,T.Sulea,E.O.Purisima

Key ref:

S.F.Chowdhury et al. (2002). Design of noncovalent inhibitors of human cathepsin L. From the 96-residue proregion to optimized tripeptides. J Med Chem, 45, 5321-5329. PubMed id: 12431059 DOI: 10.1021/jm020238t

Date:

21-Aug-02 Release date: 11-Dec-02

Protein chains

P07711  (CATL1_HUMAN) -  Cathepsin L1

Seq: 333 a.a.

Struc: 174 a.a.*

Protein chains

P07711  (CATL1_HUMAN) -  Cathepsin L1

Seq: 333 a.a.

Struc: 41 a.a.

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

Enzyme reactions

• Enzyme class: Chains A, C, B, 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: 10.1021/jm020238t

J Med Chem 45:5321-5329 (2002)

PubMed id: 12431059

Design of noncovalent inhibitors of human cathepsin L. From the 96-residue proregion to optimized tripeptides.

S.F.Chowdhury, J.Sivaraman, J.Wang, G.Devanathan, P.Lachance, H.Qi, R.Ménard, J.Lefebvre, Y.Konishi, M.Cygler, T.Sulea, E.O.Purisima.

ABSTRACT

A novel series of noncovalent inhibitors of cathepsin L have been designed to mimic the mode of autoinhibition of procathepsin L. Just like the propeptide, these peptide-based inhibitors have a reverse-binding mode relative to a substrate and span both the S' and S subsites of the enzyme active site. In contrast to previous studies in which even moderate truncation of the full-length propeptide led to rapid reduction in potency, these blocked tripeptide-sized inhibitors maintain nanomolar potency. Moreover, these short peptides show higher selectivity (up to 310-fold) for inhibiting cathepsin L over K versus only 2-fold selectivity of the 96-residue propeptide of cathepsin L. A 1.9 A X-ray crystallographic structure of the complex of cathepsin L with one of the inhibitors confirms the designed reverse-binding mode of the inhibitor as well as its noncovalent nature. Enzymatic analysis also shows the inhibitors to be resistant to hydrolysis at elevated concentrations of the enzyme. The mode of inhibition of these molecules provides a general strategy for inhibiting other cathepsins as well as other proteases.