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Conformational Plasticity of Cyclic Ras‐Inhibitor Peptides Defines Cell Permeabilization Activity
Author(s) -
Takeuchi Koh,
Misaki Imai,
Tokunaga Yuji,
Fujisaki Miwa,
Kamoshida Hajime,
Takizawa Takeshi,
Hanzawa Hiroyuki,
Shimada Ichio
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202016647
Subject(s) - chemistry , amphiphile , steric effects , peptide , cyclic peptide , dimethyl sulfoxide , biophysics , cell , conformational change , stereochemistry , biochemistry , biology , copolymer , organic chemistry , polymer
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.