The quest for high-resolution G protein-coupled receptor–G protein structures

Grisshammer, Reinhard

doi:10.1073/pnas.2002665117

Cited by 14 publications

(12 citation statements)

References 25 publications

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“…To determine whether the ionic anchors coupling the Gi protein to μOR, is restricted to μOR, we predicted the fully active state of OR-MP1104-Gi (Mafi et al, 2020) and OR-DPI-287-Gi complexes. To predict these complexes, we followed our recent procedure (Grisshammer, 2020;Mafi et al, 2020) in which we removed the mimetic G protein nanobody from the active conformation of OR (PDB ID: 6B73) (Che et al, 2018) and OR (PDB ID: 6PT2) (Claff et al, 2019), and replaced it with our optimized Gi protein bound to the mouse μOR. Subsequently, we relaxed the resulting constructs by performing MD simulations to obtain the optimized active state complexes (full details provided in the SI).…”

Section: Resultsmentioning

confidence: 99%

The G protein-first activation mechanism of opioid receptors by Gi protein and agonists

2021

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We report the G-Protein-First mechanism for activation of G protein-coupled receptors (GPCR) for the three closely subtypes of the opioid receptors (OR), h μOR, OR, and OR. We find that they couple to the inactive Gi protein-bound guanosine diphosphate (GDP) prior to agonist binding. The inactive Gi protein forms anchors to the intracellular loops of the inactive apo-μOR, apo-OR, and apo-OR, inducing opening of the cytoplasmic region to form a pre-activated state that holds Gi protein in place until agonist binds. Then, agonist binds to μOR, OR, and OR already complexed with Gi protein, to trigger the Gi to open up the tightly coupled GDP binding site, making GDP accessible for GTP exchange, an essential step for Gi signaling. We show that the agonist alone cannot open the intracellular region of μOR and OR, requiring Gi protein to open the cytoplasmic region by itself. We consider that this G Protein-First mechanism may apply to activation of other Class A GPCRs. However, for OR, agonist binding can open up the intracellular region to encourage Gi protein recruitment. Thus, activation of Gi protein mediated by OR favorably may proceed with either Ligand-First or G Protein-First activation mechanisms.

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Section: Resultsmentioning

confidence: 99%

The G protein-first activation mechanism of opioid receptors by Gi protein and agonists

2021

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“…The presented receptor model is generated using available huNK1R receptor [59,60,68] templates. The tiTac3Ra as observed belongs to the class A GPCR (Rhodopsin) family [58,63,69] and exhibits seven transmembrane domains (TM1-7) sequentially connected by Figure 9. In vivo effect of NKB antagonist, SB-222200, (Blue) compared to control group (Black) on sperm production and volume.…”

Section: Discussionmentioning

confidence: 99%

“…The presented receptor model is generated using available huNK1R receptor [59,60,68] templates. The tiTac3Ra as observed belongs to the class A GPCR (Rhodopsin) family [58,63,69] and exhibits seven transmembrane domains (TM1-7) sequentially connected by intracellular (ICL1-3) and extracellular loops (EXL1-3) and an extracellular (EXD) and a cytosolic domain containing amphiphatic helix 8 (ICD) accordingly. Extracellular tips of TM1, 4, 5 and 7 TM helices diverged towards the central GPCR transmembrane axis forming the binding cavity.…”

Section: Discussionmentioning

confidence: 99%

Characteristics of Neurokinin-3 Receptor and Its Binding Sites by Mutational Analysis

Atre

Mizrahi

Levavi‐Sivan

2021

Biology

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NKB (Neurokinin B) is already known to play a crucial role in fish reproduction, but little is known about the structure and function of NKB receptors. Based on an in silico model of the tilapia NKB receptor Tachykinin 3 receptor a (tiTac3Ra) found in the current study, we determined the key residues involved in binding to tilapia NKB and its functional homologue NKF (Neurokinin F). Despite studies in humans suggesting the crucial role of F2516.44 and M2897.43 in NKB binding, no direct peptide interaction was observed in tilapia homologs. In-silico, Ala mutations on residues F2516.44 and M2897.43 did not influence binding affinity, but significantly affected the stability of tiTac3Ra. Moreover, in vitro studies indicated them to be critical to tiNKB/tiNKF-induced receptor activity. The binding of NKB antagonists to tiTac3Ra both in-vitro and in vivo inhibits FSH (follicle stimulating hormone) and LH (luteinizing hormone) release and sperm production in mature tilapia males. Non-peptide NKB antagonist SB-222200 had a strong inhibitory effect on the Tac3Ra activation. SB-222200 also decreased LH plasma levels; two hours post intraperitoneal injection, changed sperm volume and the ratios of the different stages along the spermatogenesis in tilapia testes.

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“…Since the first high-resolution structures of the β2 adrenergic receptors-Gs complex [ 335 , 336 ], the structural studies on GPCRs and GPCR-transducer complexes have provided considerable insights into their ligand-activation and allosteric mechanisms of G protein-coupled receptor activation (reviewed in: [ 17 , 334 , 337 , 338 , 339 , 340 , 341 ]). Allostery reciprocally modulates the behaviours of GPCRs and the G-proteins: ligand binding on the extracellular side of the receptor promotes the G protein binding on the GPCR intracellular side, and the G protein increases the GPCR affinity for the ligand.…”

Section: Cell Signalling and Sensory Motricitymentioning

confidence: 99%

Towards the Idea of Molecular Brains

Timsit

Sergeant-Perthuis

2021

IJMS

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How can single cells without nervous systems perform complex behaviours such as habituation, associative learning and decision making, which are considered the hallmark of animals with a brain? Are there molecular systems that underlie cognitive properties equivalent to those of the brain? This review follows the development of the idea of molecular brains from Darwin’s “root brain hypothesis”, through bacterial chemotaxis, to the recent discovery of neuron-like r-protein networks in the ribosome. By combining a structural biology view with a Bayesian brain approach, this review explores the evolutionary labyrinth of information processing systems across scales. Ribosomal protein networks open a window into what were probably the earliest signalling systems to emerge before the radiation of the three kingdoms. While ribosomal networks are characterised by long-lasting interactions between their protein nodes, cell signalling networks are essentially based on transient interactions. As a corollary, while signals propagated in persistent networks may be ephemeral, networks whose interactions are transient constrain signals diffusing into the cytoplasm to be durable in time, such as post-translational modifications of proteins or second messenger synthesis. The duration and nature of the signals, in turn, implies different mechanisms for the integration of multiple signals and decision making. Evolution then reinvented networks with persistent interactions with the development of nervous systems in metazoans. Ribosomal protein networks and simple nervous systems display architectural and functional analogies whose comparison could suggest scale invariance in information processing. At the molecular level, the significant complexification of eukaryotic ribosomal protein networks is associated with a burst in the acquisition of new conserved aromatic amino acids. Knowing that aromatic residues play a critical role in allosteric receptors and channels, this observation suggests a general role of π systems and their interactions with charged amino acids in multiple signal integration and information processing. We think that these findings may provide the molecular basis for designing future computers with organic processors.

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The quest for high-resolution G protein-coupled receptor–G protein structures

Cited by 14 publications

References 25 publications

The G protein-first activation mechanism of opioid receptors by Gi protein and agonists

The G protein-first activation mechanism of opioid receptors by Gi protein and agonists

Characteristics of Neurokinin-3 Receptor and Its Binding Sites by Mutational Analysis

Towards the Idea of Molecular Brains

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