9DNM

Structure of rat beta-arrestin 1 bound to allosteric inhibitor

Summary for 9DNM

• Entry DOI: 10.2210/pdb9dnm/pdb
• Related: 9DNG
• EMDB information: 47040 47042
• Descriptor: anti-BRIL Fab Heavy chain, anti-BRIL Fab Light chain, Beta-arrestin-1,Soluble cytochrome b562, ... (4 entities in total)
• Functional Keywords: gpcr signaling, arrestin, allostery, signaling protein, signaling protein-immune system complex, signaling protein/immune system
• Biological source: Homo sapiens; More
• Total number of polymer chains: 3
• Total formula weight: 103208.08

Authors

Pakharukova, N.,Kahsai, A.W.,Masoudi, A.,Lefkowitz, R.J. (deposition date: 2024-09-17, release date: 2025-01-22, Last modification date: 2025-07-16)

Primary citation

Kahsai, A.W.,Pakharukova, N.,Kwon, H.Y.,Shah, K.S.,Liang-Lin, J.G.,Del Real, C.T.,Shim, P.J.,Lee, M.A.,Ngo, V.A.,Shreiber, B.N.,Liu, S.,Schwalb, A.M.,Espinoza, E.F.,Thomas, B.N.,Kunzle, C.A.,Smith, J.S.,Wang, J.,Kim, J.,Zhang, X.,Rockman, H.A.,Thomsen, A.R.B.,Rein, L.A.M.,Shi, L.,Ahn, S.,Masoudi, A.,Lefkowitz, R.J.
Small-molecule modulation of beta-arrestins.
Biorxiv, 2025

PubMed Abstract: β-arrestins are multifunctional regulators of G protein-coupled receptor (GPCR) signaling, orchestrating diverse downstream signaling events and physiological responses across the vast GPCR superfamily. While GPCR pharmacology has advanced to target orthosteric and allosteric sites, as well as G proteins and GRKs, comparable chemical tools to study β-arrestins remain lacking. Here, we report the discovery of small-molecule inhibitors that selectively target β-arrestins and delineate their mechanism of action through integrated pharmacological, biochemical, biophysical, and structural analyses. These inhibitors disrupt β-arrestin-engagement with agonist-activated GPCRs, impairing desensitization, internalization, and β-arrestin-dependent functions while sparing G protein-receptor coupling. Cryo-EM, MD simulations, and structure-guided mutagenesis reveal that one modulator, Cmpd-5, engages a cryptic pocket formed by the middle, C-, and lariat loops of β-arrestin1-a critical receptor-binding interface-stabilizing a distinct conformation incompatible with GPCR engagement. Together, these findings provide a mechanistic framework for β-arrestin modulation, introducing transducer-targeted strategies to fine-tune GPCR signaling and guide the development of pathway-specific therapeutics.

PubMed: 39763753
DOI: 10.1101/2024.12.27.630464

Experimental method

ELECTRON MICROSCOPY (3.47 Å)