The structure of beta-arrestin

Brian Kobilka group (Stanford University) and collaborators


G protein-coupled receptors (GPCRs) are critically regulated by multifunctional scaffolding proteins called beta-arrestins. The structural basis of GPCR-beta-arrestin interaction and beta-arrestin activation was lacking, but the labs of Brian Kobilka and of Robert Lefkowitz collaborated to solve the structure of activated beta-arrestin 1 to 2.6-Å resolution in complex with a phosphopeptide corresponding to the phosphorylated carboxy-terminus of the human vasopressin receptor. The X-ray diffraction data were collected at the GM/CA@APS beamline 23ID-D. The structure of activated beta-arrestin reveals a potentially universal docking interface for phosphorylated GPCRs and shows how the activation switches are turned on during the transition of beta-arretsin from inactive (or basal) to active state. This finding not only provides a structural basis for GPCR-beta-arrestin interaction, but it also reveals a potentially novel drug-binding interface.

Figure: Surface representation of activated beta-arrestin 1 showing a potentially universal groove (positively charged residues in blue) and binding of the vasopressin receptor carboxy-terminal phosphopetide (in green). The phosphorylated amino acids are shown as red spheres.


Shukla, AK, Manglik, A, Kruse, AC, Xiao, K, Reis, RI, Tseng, WC, Staus, DP, Hilger, D, Uysal, S, Huang, LY, Paduch, M, Tripathi-Shukla, P, Koide, A, Koide, S, Weis, WI, Kossiakoff, AA, Kobilka, BK, Lefkowitz, RJ. Structure of active beta-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide, Nature 497, 137-141 (2013).



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