PDBsum entry 4gly

Hydrolase/hydrolase inhibitor

PDB id: 4gly

Contents

Protein chains

245 a.a.

14 a.a.

Ligands

SO4 ×4

P6G

GOL

Metals

_NA ×2

_CL ×3

Waters ×310

References listed in PDB file

Key reference

• Title: Bicyclic peptide ligands pulled out of cysteine-Rich peptide libraries.
• Authors: S.Chen, I.Rentero rebollo, S.A.Buth, J.Morales-Sanfrutos, J.Touati, P.G.Leiman, C.Heinis.
• Ref.: J Am Chem Soc, 2013, 135, 6562-6569. [DOI no: 10.1021/ja400461h]
• PubMed id: 23560397

Abstract

Bicyclic peptide ligands were found to have good binding affinity and target specificity. However, the method applied to generate bicyclic ligands based on phage-peptide alkylation is technically complex and limits its application to specialized laboratories. Herein, we report a method that involves a simpler and more robust procedure that additionally allows screening of structurally more diverse bicyclic peptide libraries. In brief, phage-encoded combinatorial peptide libraries of the format XmCXnCXoCXp are oxidized to connect two pairs of cysteines (C). This allows the generation of 3 × (m + n + o + p) different peptide topologies because the fourth cysteine can appear in any of the (m + n + o + p) randomized amino acid positions (X). Panning of such libraries enriched strongly peptides with four cysteines and yielded tight binders to protein targets. X-ray structure analysis revealed an important structural role of the disulfide bridges. In summary, the presented approach offers facile access to bicyclic peptide ligands with good binding affinities.