9BRI

Crystal Structure of Human G Protein-Coupled Receptor Kinase 5 in Complex with GRL064-22

This is a non-PDB format compatible entry.

Summary for 9BRI

• Entry DOI: 10.2210/pdb9bri/pdb
• Descriptor: G protein-coupled receptor kinase 5, (3Z)-3-[(3,5-dimethyl-4-{[(2S)-5-oxooxolane-2-carbonyl]amino}-1H-pyrrol-2-yl)methylidene]-N-[(1R)-1-(4-fluorophenyl)ethyl]-2-oxo-2,3-dihydro-1H-indole-5-carboxamide (3 entities in total)
• Functional Keywords: g protein-coupled receptor, gpcr g protein-coupled receptor kinase, grk kinase, signaling protein-inhibitor complex, signaling protein/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 69462.27

Authors

Chen, Y.,Tesmer, J.J.G. (deposition date: 2024-05-11, release date: 2025-02-19)

Primary citation

Ghosh, A.K.,Chen, Y.,Gadi, R.K.,Sonawane, A.,Gamage, S.P.,Tesmer, J.G.
Design, synthesis, and X-ray structural studies of a series of highly potent, selective, and drug-like G protein-coupled receptor kinase 5 inhibitors.
Eur.J.Med.Chem., 282:117024-117024, 2025

PubMed Abstract: G protein-coupled receptor kinase 5 (GRK5) has emerged as a potential drug development target against heart failure and cancer. A close homolog, GRK6 represents a therapeutic target for multiple myeloma. We have rationally designed a series of highly selective, potent, noncovalent, and drug-like GRK5 inhibitors. Several inhibitors exhibited low nanomolar GRK5 inhibition and high selectivity over GRK2, and, surprisingly, some were selective for GRK6. We determined high-resolution X-ray crystal structures of several inhibitors in complex with GRK5, which provide molecular insights into the ligand-binding site interactions responsible for GRK5 selectivity and potency.

PubMed: 39549325
DOI: 10.1016/j.ejmech.2024.117024

Experimental method

X-RAY DIFFRACTION (2.9 Å)