5MWJ

Structure Enabled Discovery of a Stapled Peptide Inhibitor to Target the Oncogenic Transcriptional Repressor TLE1

Summary for 5MWJ

• Entry DOI: 10.2210/pdb5mwj/pdb
• Descriptor: Transducin-like enhancer protein 1, DIMETHYL SULFOXIDE, pepide inhibtor, ... (4 entities in total)
• Functional Keywords: transducin-like; constrained peptide inhibitor; transcriptional corepressor, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 75475.07

Authors

McGrath, S.,Tortorici, M.,Vidler, L.,Drouin, L.,Westwood, I.,Gimeson, P.,Van Montfort, R.,Hoelder, S. (deposition date: 2017-01-18, release date: 2017-04-05, Last modification date: 2024-01-17)

Primary citation

McGrath, S.,Tortorici, M.,Drouin, L.,Solanki, S.,Vidler, L.,Westwood, I.,Gimeson, P.,Van Montfort, R.,Hoelder, S.
Structure-Enabled Discovery of a Stapled Peptide Inhibitor to Target the Oncogenic Transcriptional Repressor TLE1.
Chemistry, 23:9577-9584, 2017

PubMed Abstract: TLE1 is an oncogenic transcriptional co-repressor that exerts its repressive effects through binding of transcription factors. Inhibition of this protein-protein interaction represents a putative cancer target, but no small-molecule inhibitors have been published for this challenging interface. Herein, the structure-enabled design and synthesis of a constrained peptide inhibitor of TLE1 is reported. The design features the introduction of a four-carbon-atom linker into the peptide epitope found in many TLE1 binding partners. A concise synthetic route to a proof-of-concept peptide, cycFWRPW, has been developed. Biophysical testing by isothermal titration calorimetry and thermal shift assays showed that, although the constrained peptide bound potently, it had an approximately five-fold higher K than that of the unconstrained peptide. The co-crystal structure suggested that the reduced affinity was likely to be due to a small shift of one side chain, relative to the otherwise well-conserved conformation of the acyclic peptide. This work describes a constrained peptide inhibitor that may serve as the basis for improved inhibitors.

PubMed: 28326635
DOI: 10.1002/chem.201700747

Experimental method

X-RAY DIFFRACTION (2.04 Å)