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TM5-TM6: structural switches that modulate the coupling of serotonin receptors to Gs or Gi

Updated: Nov 15, 2022

What is the molecular basis that determines that GPCRs bind selectively or promiscuously to different G proteins?. This question led Huang et al., 2022 to investigate the molecular basis involved in G protein-receptor interactions, particularly the differences between Gs and Gi/o coupling. Through Cryo-Electron Microscopy, authors reported the structures of four protein complexes integrated by a complete human serotonin receptor subtype and a dominant negative form of Gs or Gi: 5-HT4, 5-HT6, and 5-HT7 with Gs, and 5-HT4 with Gi1. Prior to this report we did not know how different serotonin receptor subtypes which share high sequence homology, coupled to different families of G proteins, so the comparison and structural analysis of these complexes revealed two important aspects: the specific residues involved in ligand selectivity and the interactions involved in the coupling of G proteins. The binding pockets for serotonin were virtually identical between the receptor-Gs and receptor-Gi complexes, suggesting that the selectivity of the G-protein lies in intrinsic features of the receptor rather than in a serotonin-induced mechanism. The discovery of the orthosteric binding pocket is of great importance in GPCRs field as it supports the development of alternatives to improve drug design to optimize receptor selectivity.

In the same way, as in other GPCRs-G protein complexes, the structural analysis revealed that electrostatic interactions are crucial for the coupling of G-proteins to serotonin receptors. The structural differences found between the receptor-Gs and receptor-Gi complexes evidenced that 5-HT4/6/7-Gs coupled receptors have a cytosolic TM5 that is on average 5.7 residues longer and a TM6 that is 7.5 residues shorter compared to 5-HT1/4 receptors that couple to Gi/o. The TM5 extension of receptors Gs-coupled provides unique interactions that are not seen in complexes formed with Gi. These differences are mainly attributed to the characteristic Ras domain distance between Gs and Gi. Therefore the authors propose that the relative lengths of TM5 and TM6 in serotonin receptors function as a macro-switch to determine the selectivity of coupling between Gs or Gi/o. Additionally, structural analysis of the TM5 and TM6 regions of 27 class A GPCRs coupled to Gs or Gi/o yielded similar results, TM5 was 5.6 ± 1.5 residues longer while TM6 was 2.6 ± 1.6 residues shorter, concluding that the TM5-TM6 macro-switch length is conserved in class A GPCRs.

Likewise, in this work the authors identify for the first time the specific amino acids that modulate the selectivity of coupling to Gs and Gi/o, reporting the presence of conserved residues for each type of G protein. The differences found at the residue level are referred to as micro-switches that will define a selective or promiscuous coupling of the receptor to the G protein. Interestingly, in the case of promiscuous receptors they found that these receptors shared conserved residues of both G protein families, suggesting that receptors that activate both Gs and Gi/o do so by combining the properties of the conserved residues with a mixture of Gs and Gi/o specific properties. These findings contribute to progress in understanding how serotonin receptors, one of the largest subfamilies of class A GPCRs and potential therapeutic targets that are activated by the same endogenous ligand, create a wide diversity of cellular responses.

Check the original article at this link

*Above information was taken from the original article published by Huang et al., 2022.

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