Conformational Plasticity of Cyclic Ras‐Inhibitor Peptides Defines Cell Permeabilization Activity. Issue 12 (16th February 2021)

• Record Type: Journal Article
• Authors: Takeuchi, Koh; Misaki, Imai; Tokunaga, Yuji; Fujisaki, Miwa; Kamoshida, Hajime; Takizawa, Takeshi; Hanzawa, Hiroyuki; Shimada, Ichio
• Is Part Of: Angewandte Chemie international edition. Volume 60:Issue 12(2021)
• Page Start: 6567
• Page End: 6572
• Publication Date: 2021-02-16
• Subjects: cell permeabilization -- NMR spectroscopy -- peptides -- protein-protein interaction inhibitor -- structure; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.202016647
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Cyclorasins 9A5 and 9A54 are 11‐mer cyclic peptides that inhibit the Ras‐Raf protein interaction. The peptides share a cell‐penetrating peptide (CPP)‐like motif; however, only cyclorasin 9A5 can permeabilize cells to exhibit strong cell‐based activity. To unveil the structural origin underlying their distinct cellular permeabilization activities, we compared the three‐dimensional structures of cyclorasins 9A5 and 9A54 in water and in the less polar solvent dimethyl sulfoxide (DMSO) by solution NMR. We found that cyclorasin 9A5 changes its extended conformation in water to a compact amphipathic structure with converged aromatic residues surrounded by Arg residues in DMSO, which might contribute to its cell permeabilization activity. However, cyclorasin 9A54 cannot adopt this amphipathic structure, due to the steric hindrance between two neighboring bulky amino‐acid sidechains, Tle‐2 and dVal‐3. We also found that the bulkiness of the sidechains at positions 2 and 3 negatively affects the cell permeabilization activities, indicating that the conformational plasticity that allows the peptides to form the amphipathic structure is important for their cell permeabilization activities. Abstract : Conformational plasticity defines cell permeabilization activity: Cell permeabilization activities of cyclic Ras‐inhibitor peptides are determined by the ability to adopt a cell‐permeable amphipathic conformation, in which aromatic residues (green) are converged on one side and the Arg residues (blue) surround the aromatic residues, in a low polarity environment.