9GRM

Cdc42 in complex with inhibitory peptide

9GRM の概要

• エントリーDOI: 10.2210/pdb9grm/pdb
• NMR情報: BMRB: 34958
• 分子名称: Cell division control protein 42 homolog, PRO-SER-ILE-CYS-HIS-VAL-HIS-ARG-PRO-ASP-TRP-PRO-CYS-ALA-TYR-ARG, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (5 entities in total)
• 機能のキーワード: inhibitor, gtpase, cytoskeletal regulator, cell cycle
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 22926.30

構造登録者

Mott, H.R.,Owen, D.,Murphy, N.P. (登録日: 2024-09-11, 公開日: 2026-01-21, 最終更新日: 2026-02-18)

主引用文献

Murphy, N.P.,Tetley, G.J.N.,Revell, J.,Mott, H.R.,Owen, D.
Cyclized Peptide Inhibitors of the Small G Protein Cdc42 Mimic Binding of Effector Proteins.
Biochemistry, 65:297-310, 2026

PubMed Abstract: The Ras superfamily of small GTPases are challenging targets for therapeutic inhibition, partially due to a lack of pockets amenable to small molecule inhibition. Our previous work identified high-affinity cyclized peptide binders of Cdc42, a member of the Rho family of small GTPases, capable of inhibiting activity. To further optimize these Cdc42 inhibitors, we have engineered modifications to the best sequence available from the original maturation and screened the ability of these third-generation peptides to compete with Cdc42-effector interactions. Improvements in affinity were achieved by single amino acid substitutions at several residue positions. We present the structure of one of these nanomolar affinity, cyclized peptides in complex with Cdc42. The structure reveals that the peptide binds in a β-hairpin conformation to create an extension of the β-sheet of the GTPase Rossman fold, acting as a structural mimic of native Cdc42 effectors. We additionally elucidate the NMR structures of four unbound C-terminal alanine variants and employ both the bound and unbound structures to inform the rational design of substituted peptide inhibitors. Overall, this study expands our understanding of how Ras GTPases can be targeted, by demonstrating a rare example of an inhibitor binding contiguously with a surface of β-strand of the small G protein, which illustrates an innovative avenue for noncovalent therapeutic design.

PubMed: 41566164
DOI: 10.1021/acs.biochem.5c00616

実験手法

SOLUTION NMR