6R28

Structure of peptide P7, which binds Cdc42 and inhibits effector interactions.

Summary for 6R28

• Entry DOI: 10.2210/pdb6r28/pdb
• NMR Information: BMRB: 34380
• Descriptor: peptide P7 (1 entity in total)
• Functional Keywords: inhibitor, cyclic peptide, synthetic peptide., de novo protein
• Biological source: synthetic construct
• Total number of polymer chains: 1
• Total formula weight: 2070.40

Authors

Murphy, N.P.,Mott, H.R.,Owen, D. (deposition date: 2019-03-15, release date: 2020-01-29, Last modification date: 2024-11-06)

Primary citation

Tetley, G.J.N.,Murphy, N.P.,Bonetto, S.,Ivanova-Berndt, G.,Revell, J.,Mott, H.R.,Cooley, R.N.,Owen, D.
The discovery and maturation of peptide biologics targeting the small G-protein Cdc42: A bioblockade for Ras-driven signaling.
J.Biol.Chem., 295:2866-2884, 2020

PubMed Abstract: Aberrant Ras signaling drives 30% of cancers, and inhibition of the Rho family small GTPase signaling has been shown to combat Ras-driven cancers. Here, we present the discovery of a 16-mer cyclic peptide that binds to Cdc42 with nanomolar affinity. Affinity maturation of this sequence has produced a panel of derived candidates with increased affinity and modulated specificity for other closely-related small GTPases. The structure of the tightest binding peptide was solved by NMR, and its binding site on Cdc42 was determined. Addition of a cell-penetrating sequence allowed the peptides to access the cell interior and engage with their target(s), modulating signaling pathways. In Ras-driven cancer cell models, the peptides have an inhibitory effect on proliferation and show suppression of both invasion and motility. As such, they represent promising candidates for Rho-family small GTPase inhibitors and therapeutics targeting Ras-driven cancers. Our data add to the growing literature demonstrating that peptides are establishing their place in the biologics arm of drug discovery.

PubMed: 31959628
DOI: 10.1074/jbc.RA119.010077

Experimental method

SOLUTION NMR