PDBsum entry 4mzs

Hydrolase/hydrolase inhibitor

PDB id: 4mzs

Contents

Protein chains

218 a.a.

Ligands

2EV ×2

Waters ×275

PDB id:

4mzs

Name:

Hydrolase/hydrolase inhibitor

Title:

Mouse cathepsin s with covalent ligand (3s,4s)-1-[(2-chlorophenyl) sulfonyl]-n-[(2e)-2-iminoethyl]-4-(morpholin-4-ylcarbonyl) pyrrolidine-3-carboxamide

Structure:

Cathepsin s. Chain: a, b. Fragment: residues 116-340. Engineered: yes

Source:

Mus musculus. Mouse. Organism_taxid: 10090. Gene: ctss, cats. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.85Å R-factor: 0.226 R-free: 0.270

Authors:

A.Kuglstatter,M.Stihle

Key ref:

H.Hilpert et al. (2013). Identification of potent and selective cathepsin S inhibitors containing different central cyclic scaffolds. J Med Chem, 56, 9789-9801. PubMed id: 24224654 DOI: 10.1021/jm401528k

Date:

30-Sep-13 Release date: 20-Aug-14

Protein chains

O70370  (CATS_MOUSE) -  Cathepsin S from Mus musculus

Seq: 340 a.a.

Struc: 218 a.a.*

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

Enzyme reactions

• Enzyme class: E.C.3.4.22.27 - cathepsin S.
• Reaction: Similar to cathepsin L, but with much less activity on Z-Phe-Arg-|-NHMec, and more activity on the Z-Val-Val-Arg-|-Xaa compound.

DOI no: 10.1021/jm401528k

J Med Chem 56:9789-9801 (2013)

PubMed id: 24224654

Identification of potent and selective cathepsin S inhibitors containing different central cyclic scaffolds.

H.Hilpert, H.Mauser, R.Humm, L.Anselm, H.Kuehne, G.Hartmann, S.Gruener, D.W.Banner, J.Benz, B.Gsell, A.Kuglstatter, M.Stihle, R.Thoma, R.A.Sanchez, H.Iding, B.Wirz, W.Haap.

ABSTRACT

Starting from the weakly active dual CatS/K inhibitor 5, structure-based design supported by X-ray analysis led to the discovery of the potent and selective (>50 000-fold vs CatK) cyclopentane derivative 22 by exploiting specific ligand-receptor interactions in the S2 pocket of CatS. Changing the central cyclopentane scaffold to the analogous pyrrolidine derivative 57 decreased the enzyme as well as the cell-based activity significantly by 24- and 69-fold, respectively. The most promising scaffold identified was the readily accessible proline derivative (e.g., 79). This compound, with an appealing ligand efficiency (LE) of 0.47, included additional structural modifications binding in the S1 and S3 pockets of CatS, leading to favorable in vitro and in vivo properties. Compound 79 reduced IL-2 production in a transgenic DO10.11 mouse model of antigen presentation in a dose-dependent manner with an ED50 of 5 mg/kg.