7KPM

Crystal structure of hEphB1 bound with ADP

7KPM の概要

• エントリーDOI: 10.2210/pdb7kpm/pdb
• 分子名称: Ephrin type-B receptor 1, ADENOSINE-5'-DIPHOSPHATE (3 entities in total)
• 機能のキーワード: hephb1, adp, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32250.66

構造登録者

Ahmed, M.,Wang, P.,Sadek, H. (登録日: 2020-11-11, 公開日: 2021-03-10, 最終更新日: 2024-10-23)

主引用文献

Ahmed, M.S.,Wang, P.,Nguyen, N.U.N.,Nakada, Y.,Menendez-Montes, I.,Ismail, M.,Bachoo, R.,Henkemeyer, M.,Sadek, H.A.,Kandil, E.S.
Identification of tetracycline combinations as EphB1 tyrosine kinase inhibitors for treatment of neuropathic pain.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed Abstract: Previous studies have demonstrated that the synaptic EphB1 receptor tyrosine kinase is a major mediator of neuropathic pain, suggesting that targeting the activity of this receptor might be a viable therapeutic option. Therefore, we set out to determine if any FDA-approved drugs can act as inhibitors of the EphB1 intracellular catalytic domain. An in silico screen was first used to identify a number of tetracycline antibiotics which demonstrated potential docking to the ATP-binding catalytic domain of EphB1. Kinase assays showed that demeclocycline, chlortetracycline, and minocycline inhibit EphB1 kinase activity at low micromolar concentrations. In addition, we cocrystallized chlortetracycline and EphB1 receptor, which confirmed its binding to the ATP-binding domain. Finally, in vivo administration of the three-tetracycline combination inhibited the phosphorylation of EphB1 in the brain, spinal cord, and dorsal root ganglion (DRG) and effectively blocked neuropathic pain in mice. These results indicate that demeclocycline, chlortetracycline, and minocycline can be repurposed for treatment of neuropathic pain and potentially for other indications that would benefit from inhibition of EphB1 receptor kinase activity.

PubMed: 33627480
DOI: 10.1073/pnas.2016265118

実験手法

X-RAY DIFFRACTION (1.608 Å)