8T09

Co-crystal structure of KRIT1 with a 1-hydroxy 2-naphthaldehyde derivative (6-ethynyl-2-hydroxy-1-naphthaldehyde)

8T09 の概要

• エントリーDOI: 10.2210/pdb8t09/pdb
• 関連するPDBエントリー: 8SU8
• 分子名称: Krev interaction trapped protein 1, Ras-related protein Rap-1b, 6-ethynyl-2-hydroxynaphthalene-1-carbaldehyde, ... (6 entities in total)
• 機能のキーワード: complex, inhibitor, cell adhesion
• 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: 56781.14

構造登録者

Bruystens, J.G.H. (登録日: 2023-05-31, 公開日: 2023-12-13, 最終更新日: 2024-10-23)

主引用文献

Francisco, K.R.,Bruystens, J.,Varricchio, C.,McCurdy, S.,Wu, J.,Lopez-Ramirez, M.A.,Ginsberg, M.,Caffrey, C.R.,Brancale, A.,Gingras, A.R.,Hixon, M.S.,Ballatore, C.
Targeted Reversible Covalent Modification of a Noncatalytic Lysine of the Krev Interaction Trapped 1 Protein Enables Site-Directed Screening for Protein-Protein Interaction Inhibitors.
Acs Pharmacol Transl Sci, 6:1651-1658, 2023

PubMed Abstract: The covalent reversible modification of proteins is a validated strategy for the development of probes and candidate therapeutics. However, the covalent reversible targeting of noncatalytic lysines is particularly challenging. Herein, we characterize the 2-hydroxy-1-naphthaldehyde (HNA) fragment as a targeted covalent reversible ligand of a noncatalytic lysine (Lys) of the Krev interaction trapped 1 (KRIT1) protein. We show that the interaction of HNA with KRIT1 is highly specific, results in prolonged residence time of >8 h, and inhibits the Heart of glass 1 (HEG1)-KRIT1 protein-protein interaction (PPI). Screening of HNA derivatives identified analogs exhibiting similar binding modes as the parent fragment but faster target engagement and stronger inhibition activity. These results demonstrate that HNA is an efficient site-directing fragment with promise in developing HEG1-KRIT1 PPI inhibitors. Further, the aldimine chemistry, when coupled with templating effects that promote proximity, can produce a long-lasting reversible covalent modification of noncatalytic lysines.

PubMed: 37974623
DOI: 10.1021/acsptsci.3c00156

実験手法

X-RAY DIFFRACTION (2.15 Å)