7KPM

Crystal structure of hEphB1 bound with ADP

Summary for 7KPM

• Entry DOI: 10.2210/pdb7kpm/pdb
• Descriptor: Ephrin type-B receptor 1, ADENOSINE-5'-DIPHOSPHATE (3 entities in total)
• Functional Keywords: hephb1, adp, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 32250.66

Authors

Ahmed, M.,Wang, P.,Sadek, H. (deposition date: 2020-11-11, release date: 2021-03-10, Last modification date: 2024-10-23)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.608 Å)