6IQN

Crystal structure of TrkA kinase with ligand

6IQN の概要

• エントリーDOI: 10.2210/pdb6iqn/pdb
• 分子名称: High affinity nerve growth factor receptor, 4-[[4-azanyl-3-(4-cyclohexylpiperazin-1-yl)-9,10-bis(oxidanylidene)anthracen-1-yl]amino]benzoic acid (3 entities in total)
• 機能のキーワード: inhibitor, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 68284.88

構造登録者

Noritaka, F. (登録日: 2018-11-08, 公開日: 2020-01-22, 最終更新日: 2023-11-22)

主引用文献

Furuya, N.,Momose, T.,Katsuno, K.,Fushimi, N.,Muranaka, H.,Handa, C.,Sawa, M.,Ozawa, T.,Kinoshita, T.
An isoform-selective inhibitor of tropomyosin receptor kinase A behaves as molecular glue.
Bioorg.Med.Chem.Lett., 30:126775-126775, 2020

PubMed Abstract: The production of TrkA-selective inhibitors is considerably difficult because the kinase domains of TrkA and its isoforms TrkB/C have highly homologous amino acid sequences. Here we describe the structural basis for the acquisition of selectivity for a isoform-selective TrkA inhibitor, namely compound V1. The X-ray structure revealed that V1 acts as a molecular glue to stabilize the symmetrical dimer of the TrkA kinase domains. V1 binds to the ATP-binding site and simultaneously engages in the dimeric interface of TrkA. The region of the dimeric interface in TrkA is not conserved in TrkB/C; thus, dimer formation may be a novel mechanism for the production of selective TrkA inhibitors. The biochemical and biophysical assay results confirmed that V1 selectively inhibited TrkA and induced the dimer formation of TrkA, but not TrkB. The binding pocket at the TrkA dimer interface can be used for the production of new isoform-selective TrkA inhibitors.

PubMed: 31699609
DOI: 10.1016/j.bmcl.2019.126775

実験手法

X-RAY DIFFRACTION (2.54 Å)