PDBsum entry 4jt0

Hydrolase/hydrolase inhibitor

PDB id: 4jt0

Contents

Protein chains

250 a.a.

244 a.a.

241 a.a.

242 a.a.

233 a.a.

244 a.a.

243 a.a.

222 a.a.

204 a.a.

198 a.a.

212 a.a.

222 a.a.

233 a.a.

196 a.a.

Ligands

TY5-ALA-RE0-ABN

ACA-TY5-ALA-RE0-ABN

MES ×2

0L1

Waters ×1335

References listed in PDB file

Key reference

• Title: Dimerized linear mimics of a natural cyclopeptide (tmc-95a) are potent noncovalent inhibitors of the eukaryotic 20s proteasome.
• Authors: A.Desvergne, E.Genin, X.Maréchal, N.Gallastegui, L.Dufau, N.Richy, M.Groll, J.Vidal, M.Reboud-Ravaux.
• Ref.: J Med Chem, 2013, 56, 3367-3378. [DOI no: 10.1021/jm4002007]
• PubMed id: 23540790

Abstract

Noncovalent proteasome inhibitors introduce an alternative mechanism of inhibition to that of covalent inhibitors used in cancer therapy. Starting from a noncovalent linear mimic of TMC-95A, a series of dimerized inhibitors using polyaminohexanoic acid spacers has been designed and optimized to target simultaneously two of the six active sites of the eukaryotic 20S proteasome. The homodimerized compounds actively inhibited chymotrypsin-like (Ki = 6-11 nM) and trypsin-like activities, whereas postacid activity was poorly modified. The noncovalent binding mode was ascertained by X-ray crystallography of the inhibitors complexed with the yeast 20S proteasome. The inhibition of proteasomal activities in human cells was evaluated. The use of the multivalency inhibitor concept has produced highly efficient and selective noncovalent compounds (no inhibition of calpain and cathepsin) that have potential therapeutic advantages compared to covalent binders such as bortezomib and carfilzomib.