9BT8

Structure of Src in complex with beta-arrestin 1 revealing SH3 binding sites

Summary for 9BT8

• Entry DOI: 10.2210/pdb9bt8/pdb
• Related: 8U4H 8U7A
• EMDB information: 41882 41971 44881
• Descriptor: Proto-oncogene tyrosine-protein kinase Src, Antibody fragment Fab30, heavy chain, Vasopressin V2 receptor, ... (6 entities in total)
• Functional Keywords: gpcr signaling, arrestin, src, sh3, signaling protein-immune system complex, signaling protein
• Biological source: Gallus gallus (chicken); More
• Total number of polymer chains: 6
• Total formula weight: 164769.11

Authors

Pakharukova, N.,Bansia, H.,Bassford, D.K.,des Georges, A.,Lefkowitz, R.J. (deposition date: 2024-05-14, release date: 2024-11-13, Last modification date: 2026-03-04)

Primary citation

Pakharukova, N.,Thomas, B.N.,Bansia, H.,Li, L.,Bassford, D.K.,Abzalimov, R.R.,Kim, J.,Kahsai, A.W.,Pani, B.,Xiao, K.,Ochakovski, R.,Liu, S.,Zhang, X.,Ahn, S.,des Georges, A.,Lefkowitz, R.J.
Mechanism of beta-arrestin 1 mediated Src activation via Src SH3 domain revealed by cryo-electron microscopy.
Nat Commun, 2026

PubMed Abstract: Beta-arrestins (βarrs) are key regulators and transducers of G-protein coupled receptor signaling; however, little is known of how βarrs communicate with their downstream effectors. Here, we delineate structural mechanisms underlying βarr-mediated signal transduction. Using cryo-electron microscopy, we elucidate how βarr1 recruits and activates the non-receptor tyrosine kinase Src, a well-established signaling partner of βarrs. βarr1 engages Src SH3 through two distinct sites, each employing a different recognition mechanism: a polyproline motif in the N-domain and a non-proline-based interaction in the central crest region. At both sites βarr1 interacts with the aromatic surface of SH3, disrupting the autoinhibited conformation of Src and directly triggering its allosteric activation. This structural evidence establishes βarr1 as an active regulatory protein rather than a passive scaffold and suggests a potentially general mechanism for βarr-mediated signaling across diverse effectors.

PubMed: 41720803
DOI: 10.1038/s41467-026-69884-1

Experimental method

ELECTRON MICROSCOPY (3.34 Å)