Structures for G-Protein-Coupled Receptor Tetramers in Complex with G Proteins  Arnau Cordomí, Gemma Navarro, María S. Aymerich, Rafael Franco  Trends in Biochemical Sciences  Volume 40, Issue 10, Pages 548-551 (October 2015) DOI: 10.1016/j.tibs.2015.07.007 Copyright © 2015 The Authors Terms and Conditions

Figure 1 Likely G-Protein-Coupled Receptor (GPCR) Dimer Structures Based on 3D Data. To construct these models, we used the data summarized in Table S1 in the supplemental information online. (A) Extracellular view of representative receptor pairs superposed on a central protomer (in red). Interacting (symmetric) interfaces that may form a dimer are: TM1 (white), TM4 (gray), TM4/5 (yellow), or TM5/6 (blue). (B–G) Models of complexes formed by GPCRs and G proteins. Transmembrane (TM) helices are represented as cylinders. Apart from TM5 (in green) and TM6 (in blue), TMs of the receptor interacting with the α subunit are in dark gray and TMs of the second receptor in light gray. (B) TM5 and TM6 helices need to make room to accommodate the GαCt peptide string (orange). The cytoplasmic half of the helices of TM1, TM4, and TM4/5 dimers (C), but not TM5/6 dimers (D), can move outward (indicated by arrows). (E) Steric clash between the second protomer (light gray) in a TM4 dimer and the crystal structure of the partner receptor in complex with a G protein (α subunit in orange; GαNt indicated by a circle). (F) Coronal view from the extracellular side of a TM1 dimer interacting with a G protein (α subunit in orange and βγ in yellow). Observe the lack of complementation between βγ and the partner protomer (also occurring for TM4 dimers). (G) In each GTP–GDP cycle, the AH domain of Gα (in red) switches from a closed to an open conformation. The open AH conformation observed in the crystal structure of β2AR-Gs clashes with the second protomer of a TM4/5 dimer. Trends in Biochemical Sciences 2015 40, 548-551DOI: (10.1016/j.tibs.2015.07.007) Copyright © 2015 The Authors Terms and Conditions

Figure 2 Likely Structures for Tetramers in Complex with Two G Proteins. Except transmembrane 5 (TM5; in green) and TM6 (in blue), TMs in interacting dimers are in gray or red. The GPCRs in dark gray or dark red are those interacting with the GαCt peptide string of each of the two G proteins. (A) ‘Linear’ heterotetramer comprising two TM4/5 dimers with the TM1 interdimer interface modeled using the crystal structure of the β1-adrenergic receptor (Protein Data Bank id: 4GPO [4]. For simplicity, we used the notation TM4/5–TM1, to indicate the intradimer–interdimer interface. There are three possible ways of arranging two G proteins in such a heterotetramer (in-in, in-out, and out-out). (B) ‘Zigzagged’ TM1αTM5/6 heterotetramer with G proteins in the out-out mode modeled using the crystal structure of the μ-opioid receptor (Protein Data Bank id: 4DKL [3]). (C) ‘Compact’ TM4/5αTM5 heterotetramer with G proteins in the out-out mode. In all panels, Gα subunits are depicted in orange or pink, and the corresponding Gβγ subunits in yellow and violet, respectively. Trends in Biochemical Sciences 2015 40, 548-551DOI: (10.1016/j.tibs.2015.07.007) Copyright © 2015 The Authors Terms and Conditions