7OFV

NMR-guided design of potent and selective EphA4 agonistic ligands

Summary for 7OFV

• Entry DOI: 10.2210/pdb7ofv/pdb
• Descriptor: Ephrin type-A receptor 4, EphA4 agonist ligand, ACETATE ION, ... (4 entities in total)
• Functional Keywords: epha4, 150d4, ephrin, rtk, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 22275.30

Authors

Ganichkin, O.M.,Craig, T.K.,Baggio, C.,Pellecchia, M. (deposition date: 2021-05-05, release date: 2021-08-11, Last modification date: 2024-01-31)

Primary citation

Baggio, C.,Kulinich, A.,Dennys, C.N.,Rodrigo, R.,Meyer, K.,Ethell, I.,Pellecchia, M.
NMR-Guided Design of Potent and Selective EphA4 Agonistic Ligands.
J.Med.Chem., 64:11229-11246, 2021

PubMed Abstract: In this paper, we applied an innovative nuclear magnetic resonance (NMR)-guided screening and ligand design approach, named focused high-throughput screening by NMR (fHTS by NMR), to derive potent, low-molecular-weight ligands capable of mimicking interactions elicited by ephrin ligands on the receptor tyrosine kinase EphA4. The agents bind with nanomolar affinity, trigger receptor activation in cellular assays with motor neurons, and provide remarkable motor neuron protection from amyotrophic lateral sclerosis (ALS) patient-derived astrocytes. Structural studies on the complex between EphA4 ligand-binding domain and a most active agent provide insights into the mechanism of the agents at a molecular level. Together with preliminary in vivo pharmacology studies, the data form a strong foundation for the translation of these agents for the treatment of ALS and potentially other human diseases.

PubMed: 34293864
DOI: 10.1021/acs.jmedchem.1c00608

Experimental method

X-RAY DIFFRACTION (1.43 Å)