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: 2026-07-15)

Primary citation

Kahsai, A.W.,Pakharukova, N.,Kwon, H.Y.,Shah, K.S.,Del Real, C.T.,Shreiber, B.N.,Liang-Lin, J.G.,Shim, P.J.,Lee, M.A.,Ngo, V.A.,Schwalb, A.M.,Pham, U.,Chundi, A.,Jiang, H.,Flores-Espinoza, E.,Liu, S.,Nibley, P.C.,Bassford, D.K.,Hahn, H.,Kunzle, C.A.,Thomas, B.N.,Kim, J.,Zhou, Y.,Wang, J.,Zhang, X.,Smith, J.S.,Rein, L.A.M.,Thomsen, A.R.B.,Shenoy, S.K.,Rajagopal, S.,Shi, L.,Ahn, S.,Rockman, H.A.,Masoudi, A.,Lefkowitz, R.J.
Small-molecule modulation of beta-arrestins.
Nature, 2026

PubMed Abstract: β-Arrestins are multifunctional regulators of G-protein-coupled receptor (GPCR) signalling and orchestrate diverse downstream signalling events and physiological responses across the GPCR superfamily. Although GPCR pharmacology has advanced to target orthosteric and allosteric sites, as well as G proteins and GPCR kinases, direct chemical tools to modulate β-arrestin activities have remained conspicuously absent. Here we report the identification 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 physiological functions while sparing G protein-receptor coupling. Cryo-electron microscopy, molecular dynamics simulations and structure-guided mutagenesis reveal that one modulator, Cmpd-5, engages a pocket within the central crest of β-arrestin1 formed by the middle, C and lariat loops, a critical receptor-binding interface, stabilizing a distinct conformation that is incompatible with full β-arrestin-receptor engagement. Together, these findings establish a mechanistic framework for β-arrestin modulation, reveal a novel allosteric site for structure-based drug design, and open new avenues for transducer-targeted, pathway-specific GPCR therapeutic agents.

PubMed: 42343124
DOI: 10.1038/s41586-026-10683-5

Experimental method

ELECTRON MICROSCOPY (3.47 Å)