PDBsum entry 4q2k

Hydrolase/hydrolase inhibitor

PDB id: 4q2k

Contents

Protein chains

231 a.a.

Ligands

5BF ×4

Waters ×505

References listed in PDB file

Key reference

• Title: Macrocyclic protease inhibitors with reduced peptide character.
• Authors: K.C.Chua, M.Pietsch, X.Zhang, S.Hautmann, H.Y.Chan, J.B.Bruning, M.Gütschow, A.D.Abell.
• Ref.: Angew Chem Int Ed Engl, 2014, 53, 7828-7831. [DOI no: 10.1002/anie.201404301]
• PubMed id: 24903745

Abstract

There is a real need for simple structures that define a β-strand conformation, a secondary structure that is central to peptide-protein interactions. For example, protease substrates and inhibitors almost universally adopt this geometry on active site binding. A planar pyrrole is used to replace two amino acids of a peptide backbone to generate a simple macrocycle that retains the required geometry for active site binding. The resulting β-strand templates have reduced peptide character and provide potent protease inhibitors with the attachment of an appropriate amino aldehyde to the C-terminus. Picomolar inhibitors of cathepsin L and S are reported and the mode of binding of one example to the model protease chymotrypsin is defined by X-ray crystallography.