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) |
| 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 Modulators of beta-arrestins. Biorxiv, 2024 Cited by PubMed Abstract: β-arrestins (βarrs) are key regulators of G protein-coupled receptors (GPCRs), essential for modulating signaling pathways and physiological processes. While current pharmacological strategies target GPCR orthosteric and allosteric sites, as well as G protein transducers, comparable tools for studying βarrs are lacking. Here, we present the discovery and characterization of novel small-molecule allosteric inhibitors of βarrs through comprehensive biophysical, biochemical, pharmacological, and structural analyses. These inhibitors disrupt βarr interactions with agonist-activated GPCRs, impairing receptor internalization, desensitization, and βarr-mediated physiological functions. A cryo-EM structure of βarr1 in complex with the allosteric inhibitor Cmpd-5, complemented by molecular dynamics simulations and mutagenesis studies, reveals that Cmpd-5 binds within a cryptic cleft formed by the middle, C-, and lariat loops-a critical site for βarr activation and recruitment to GPCRs. Thus, Cmpd-5 acts as a molecular lock, hindering βarr1 activation via an allosteric mechanism. These findings introduce novel strategies and tools for probing βarr functions. PubMed: 39763753DOI: 10.1101/2024.12.27.630464 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.47 Å) |
Structure validation
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