6umw | pdb_00006umw
Crystal structure of hEphB1 bound with chlortetracycline
Structural highlights
Function[EPHB1_HUMAN] Receptor tyrosine kinase which binds promiscuously transmembrane ephrin-B family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Cognate/functional ephrin ligands for this receptor include EFNB1, EFNB2 and EFNB3. During nervous system development, regulates retinal axon guidance redirecting ipsilaterally ventrotemporal retinal ganglion cells axons at the optic chiasm midline. This probably requires repulsive interaction with EFNB2. In the adult nervous system together with EFNB3, regulates chemotaxis, proliferation and polarity of the hippocampus neural progenitors. Beside its role in axon guidance plays also an important redundant role with other ephrin-B receptors in development and maturation of dendritic spines and synapse formation. May also regulate angiogenesis. More generally, may play a role in targeted cell migration and adhesion. Upon activation by EFNB1 and probably other ephrin-B ligands activates the MAPK/ERK and the JNK signaling cascades to regulate cell migration and adhesion respectively.[1] [2] [3] [4] [5] Publication Abstract from PubMedPrevious 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. Identification of tetracycline combinations as EphB1 tyrosine kinase inhibitors for treatment of neuropathic pain.,Ahmed MS, Wang P, Nguyen NUN, Nakada Y, Menendez-Montes I, Ismail M, Bachoo R, Henkemeyer M, Sadek HA, Kandil ES Proc Natl Acad Sci U S A. 2021 Mar 9;118(10). pii: 2016265118. doi:, 10.1073/pnas.2016265118. PMID:33627480[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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