Article Figures & Data
Figures
- Figure 1. Selectivity-determining residues for each Gα subtype.
(A) The formula for specific residue identification. (B) The schema describes the comparisons between paralogous human receptors to find the specifically conserved residues for each Gα. Arrows represent a single comparison. (C) The distribution of specifically conserved residues for each Gα subtype and hierarchical clustering of them (complete linkage). (D) Possible variants of Gs specific residues that are observed in non-coupler receptors are compared with the WT activity score. (E) Maximum-likelihood phylogenetic tree of aminergic receptors including coupling profiles, conservation information of selected specifically conserved residues (I, Inoue; A, Avet), The background color scale for each consensus amino acid correlates with their conservation (identity).
- Figure 2. Structural analysis of molecular pathways that are observed upon coupling with a heteromeric G protein complex.
(A) The most common molecular signal transduction pathways from ligand-binding pocket to G protein–coupling interface. The arrows represent a contact change upon coupling to a G protein. The network is summarized and divided into different layers based on their functional relevance. (B) Projection of main chains of specifically conserved and consensus residues in different layers of activation on inactive ADRB2 structure (PDB ID 2RH1). (C) The distribution of specifically conserved residues for each analyzed Gα subtype.
- Figure 3. Specific activation networks for Gs, Gi1, Go and Gq.
(A) TM6 tilt comparison between the active receptors we used. Red: Gs couplers, Orange: Go, Gi1, and Gq, Blue: 5HT1B Go coupler as an exception. (B) Interactions within the receptor that are specific (P < 0.01) to Gs. Red: increasing contact, blue: decreasing contact, orange circle: present in common activation mechanism, red fill: uniquely identified specific residue for Gs, grey fill: Gα specific residue. The width of the lines correlates with statistical significance. A group of residues that possibly facilitate in TM6 movement for Gs coupling was shown on inactive (blue) and active (red) structures. (C, D, E) Specific interaction networks for Gi1, Go, and Gq. P < 0.1 is used for Gi1. *: This interaction is identified only if 5HT1B is neglected from the comparison because of its larger TM6 movement.
- Figure 4. Analysis of molecular dynamics simulations reveals functional importance of glycine at 7x41.
(A) Four different MD simulation systems were shown in their initial conformation. (B) For each simulation, distribution of frames with respect to their state of activation was shown, distance in Angstrom. (C) The common pathway representing the impact of the mutations at 7x41. (D, E) The common pathway was represented on average structures that were obtained in all MD trajectories for every mutation and WT. The movements of residues were represented with arrows.
- Figure 5. Sequential switches of activation model for G protein selectivity.
The model describes that all switches in different layers of receptors must be turned off for receptor activation and coupling of the G protein. If switches at upper layers are halted due to a mutation, the following switches become turned off which inhibits G protein coupling eventually.
- Figure S1. Selective pathways for activation containing all conserved residues.
This network contains complete list of conserved residues for each layer we demonstrated in Fig 2B. Each layer from top to bottom is represented with a different color. Some of the nodes are lack an edge due to the filtration step that we applied based on frequency of the information change between two residues.
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