5H09

Crystal structure of HCK complexed with a pyrrolo-pyrimidine inhibitor (S)-ethyl2-(((1r,4S)-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)amino)-4-methylpentanoate

5H09 の概要

• エントリーDOI: 10.2210/pdb5h09/pdb
• 関連するPDBエントリー: 5H0A 5H0B 5H0C 5H0D 5H0E 5H0F 5H0G 5H0H
• 分子名称: Tyrosine-protein kinase HCK, ethyl (2~{S})-2-[[4-[4-azanyl-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl]amino]-4-methyl-pentanoate (3 entities in total)
• 機能のキーワード: transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Isoform 1: Lysosome. Isoform 2: Cell membrane ; Lipid-anchor . Cytoplasmic vesicle, secretory vesicle: P08631
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 52541.91

構造登録者

Tomabechi, Y.,Kukimoto-Niino, M.,Shirouzu, M. (登録日: 2016-10-04, 公開日: 2017-10-04, 最終更新日: 2024-10-23)

主引用文献

Yuki, H.,Kikuzato, K.,Koda, Y.,Mikuni, J.,Tomabechi, Y.,Kukimoto-Niino, M.,Tanaka, A.,Shirai, F.,Shirouzu, M.,Koyama, H.,Honma, T.
Activity cliff for 7-substituted pyrrolo-pyrimidine inhibitors of HCK explained in terms of predicted basicity of the amine nitrogen.
Bioorg. Med. Chem., 25:4259-4264, 2017

PubMed Abstract: We previously reported the structure-based design of a highly potent hematopoietic cell kinase (HCK) inhibitor, a pyrrolo-pyrimidine compound designated RK-20449, for treatment of recurrent leukemia. Herein we report the synthesis and structure-activity relationships of some amino acid derivatives of 7-substituted pyrrolo-pyrimidine. Although these derivatives had the same predicted binding conformation as RK-20449, their IC values were 100-1000 times larger than that of the parent compound. We assumed that the basicity of the amine nitrogen, which formed an ionic bond with Asp348 of HCK, markedly affected inhibitory activity against HCK. The pKa values of the nitrogen were predicted by means of an ab initio quantum mechanical method, and complexes of the derivatives with HCK were analyzed by X-ray crystallography. We observed a significant correlation between the predicted pKa and IC values, and the crystal structures of the less potent derivatives showed various types of defects around the ionic bond.

PubMed: 28662963
DOI: 10.1016/j.bmc.2017.05.053

実験手法

X-RAY DIFFRACTION (1.945 Å)