Structural insights into promiscuous GPCR-G protein coupling

Carrión-Antolí, Ángela; Mallor-Franco, Jorge; Arroyo-Urea, Sandra; García-Nafría, Javier

doi:10.1016/bs.pmbts.2022.06.015

Cited by 3 publications

(3 citation statements)

References 60 publications

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“…Additionally, both structures present a similar outward swing in TM6 irrespective of GO or Gi coupling (Fig. 2B-C), in line with previous observations of the same receptor coupled to different Gα proteins keeping the magnitude of TM6 outward swing 37,38 . However, differences occur when looking at the C-terminal a5 interactions of GO vs Gi.…”

Section: Activation Mechanism and Go Coupling Of The D3r Bound To Fob...supporting

confidence: 91%

Structure of the dopamine D3 receptor bound to a bitopic agonist reveals a new specificity site in an expanded allosteric pocket

García-Nafría,

Arroyo-Urea,

Nazarova

et al. 2023

Preprint

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Although aminergic GPCRs are the target for ~25% of approved drugs, developing subtype selective drugs is a major challenge due to the high sequence conservation at their orthosteric binding site. Bitopic ligands are covalently joined orthosteric and allosteric pharmacophores with the potential to boost receptor selectivity, driven by the binding of the secondary pharmacophore to non-conserved regions of the receptor. Although bitopic ligands have great potential to improve current medications by reducing off-target side effects, the lack of structural information on their binding mode impedes rational design. Here we determine the cryo-EM structure of the hD3R coupled to a Go heterotrimer and bound to the D3R selective bitopic agonist FOB02-04A. Structural, functional and computational analyses provide new insights into its binding mode and point to a new TM2-ECL1-TM1 region, which requires the N-terminal ordering of TM1, as a major determinant of subtype selectivity in aminergic GPCRs. This region is underexploited in drug development, expands the established secondary binding pocket in aminergic GPCRs and could potentially be used to design novel and subtype selective drugs.

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Section: Activation Mechanism and Go Coupling Of The D3r Bound To Fob...supporting

confidence: 91%

Structure of the dopamine D3 receptor bound to a bitopic agonist reveals a new specificity site in an expanded allosteric pocket

García-Nafría,

Arroyo-Urea,

Nazarova

et al. 2023

Preprint

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“…Cryo-EM structures of eleven GPCRs have been determined with each GPCR coupled to two or more distinct G proteins: GCGR, β 1 AR, ADGRF1 and 5HT 4 R coupled to G s and G i/o [ 10 , 11 , 12 , 13 ], NK 1 R coupled to G s and G q/11 [ 14 ], CCK A R coupled to G q , G i1 and G s [ 15 , 16 ], ADGRL3 coupled to G s , G i , G q and G 12 [ 17 ••] and four receptors coupled to G i/o and G q/11 (GSHR [ 18 , 19 ], CCK B R [ 20 ], GPR139 [ 21 ] and MRGPRX2 [ 22 ]). Several trends arise from analysing this set of structures [ 23 ].…”

Section: Structural Mechanisms In Promiscuous Gpcr-g Protein Couplingmentioning

confidence: 99%

New insights into GPCR coupling and dimerisation from cryo-EM structures

Gusach

García-Nafría

Tate

2023

Current Opinion in Structural Biology

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“…Additionally, they frequently show biased responses that amplify their meta states and functional role. The reaction of GPCRs to ligands with agonist, antagonist, inverse agonist, or allosteric properties and the binding to transducers makes these receptors susceptible to regulation in a complex and versatile fashion [121][122][123][124][125][126][127]. Consequently, drugs designed to control and modulate GPCRs have enormous potential.…”

Section: Nt Receptors Ligands As Possible Pharmacological Treatments ...mentioning

confidence: 99%

Neurotensin and Alcohol Use Disorders: Towards a Pharmacological Treatment

Rodríguez

Sánchez

Coveñas

2023

IJMS

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Harmful alcohol use is responsible for a group of disorders collectively named alcohol use disorders (AUDs), according to the DSM-5 classification. The damage induced by alcohol depends on the amount, time, and consumption patterns (continuous and heavy episodic drinking). It affects individual global well-being and social and familial environments with variable impact. Alcohol addiction manifests with different degrees of organ and mental health detriment for the individual, exhibiting two main traits: compulsive drinking and negative emotional states occurring at withdrawal, frequently causing relapse episodes. Numerous individual and living conditions, including the concomitant use of other psychoactive substances, lie in the complexity of AUD. Ethanol and its metabolites directly impact the tissues and may cause local damage or alter the homeostasis of brain neurotransmission, immunity scaffolding, or cell repair biochemical pathways. Brain modulator and neurotransmitter-assembled neurocircuitries govern reward, reinforcement, social interaction, and consumption of alcohol behaviors in an intertwined manner. Experimental evidence supports the participation of neurotensin (NT) in preclinical models of alcohol addiction. For example, NT neurons in the central nucleus of the amygdala projecting to the parabrachial nucleus strengthen alcohol consumption and preference. In addition, the levels of NT in the frontal cortex were found to be lower in rats bred to prefer alcohol to water in a free alcohol–water choice compared to wild-type animals. NT receptors 1 and 2 seem to be involved in alcohol consumption and alcohol effects in several models of knockout mice. This review aims to present an updated picture of the role of NT systems in alcohol addiction and the possible use of nonpeptide ligands modulating the activity of the NT system, applied to experimental animal models of harmful drinking behavior mimicking alcohol addiction leading to health ruin in humans.

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Structural insights into promiscuous GPCR-G protein coupling

Cited by 3 publications

References 60 publications

Structure of the dopamine D3 receptor bound to a bitopic agonist reveals a new specificity site in an expanded allosteric pocket

Structure of the dopamine D3 receptor bound to a bitopic agonist reveals a new specificity site in an expanded allosteric pocket

New insights into GPCR coupling and dimerisation from cryo-EM structures

Neurotensin and Alcohol Use Disorders: Towards a Pharmacological Treatment

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