GPCR Dynamics: Structures in Motion

Latorraca, Naomi R.; Venkatakrishnan, AJ; Dror, Ron O.

doi:10.1021/acs.chemrev.6b00177

Cited by 645 publications

(664 citation statements)

References 161 publications

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“…GPCRs are signaling machines that function by toggling between multiple conformers (Latorraca et al, 2016). The dynamic nature of GPCRs has made their crystallization process extremely challenging (Kobilka, 2013).…”

Section: Discussionmentioning

confidence: 99%

Mechanism of allosteric regulation of β2-adrenergic receptor by cholesterol

Manna

Niemelä

Tynkkynen

et al. 2016

eLife

131

149

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There is evidence that lipids can be allosteric regulators of membrane protein structure and activation. However, there are no data showing how exactly the regulation emerges from specific lipid-protein interactions. Here we show in atomistic detail how the human β2-adrenergic receptor (β2AR) – a prototypical G protein-coupled receptor – is modulated by cholesterol in an allosteric fashion. Extensive atomistic simulations show that cholesterol regulates β2AR by limiting its conformational variability. The mechanism of action is based on the binding of cholesterol at specific high-affinity sites located near the transmembrane helices 5–7 of the receptor. The alternative mechanism, where the β2AR conformation would be modulated by membrane-mediated interactions, plays only a minor role. Cholesterol analogues also bind to cholesterol binding sites and impede the structural flexibility of β2AR, however cholesterol generates the strongest effect. The results highlight the capacity of lipids to regulate the conformation of membrane receptors through specific interactions.DOI: http://dx.doi.org/10.7554/eLife.18432.001

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Section: Discussionmentioning

confidence: 99%

Mechanism of allosteric regulation of β2-adrenergic receptor by cholesterol

Manna

Niemelä

Tynkkynen

et al. 2016

eLife

131

149

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“…Specific residues in the N-terminal domain of CXCR1 contribute to both the selectivity and the affinity of the receptor for IL-8. GPCRs undergo conformational changes as a result of ligand binding and their dynamics are hypothesized to play an important role in the transmission of signals across membranes (70). The N-and C-terminal residues of the aporeceptor display evidence of mobility in several different sample preparations and NMR experiments.…”

Section: Discussionmentioning

confidence: 99%

Interaction of Monomeric Interleukin-8 with CXCR1 Mapped by Proton-Detected Fast MAS Solid-State NMR

Park

Berkamp

Radoicic

et al. 2017

Biophysical Journal

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The human chemokine interleukin-8 (IL-8; CXCL8) is a key mediator of innate immune and inflammatory responses. This small, soluble protein triggers a host of biological effects upon binding and activating CXCR1, a G proteincoupled receptor, located in the cell membrane of neutrophils. Here, we describe 1 H-detected magic angle spinning solid-state NMR studies of monomeric IL-8 (1-66) bound to full-length and truncated constructs of CXCR1 in phospholipid bilayers under physiological conditions. Cross-polarization experiments demonstrate that most backbone amide sites of IL-8 (1-66) are immobilized and that their chemical shifts are perturbed upon binding to CXCR1, demonstrating that the dynamics and environments of chemokine residues are affected by interactions with the chemokine receptor. Comparisons of spectra of IL-8 (1-66) bound to full-length CXCR1 (1-350) and to N-terminal truncated construct NT-CXCR1 (39-350) identify specific chemokine residues involved in interactions with binding sites associated with N-terminal residues (binding site-I) and extracellular loop and helical residues (binding site-II) of the receptor. Intermolecular paramagnetic relaxation enhancement broadening of IL-8 (1-66) signals results from interactions of the chemokine with CXCR1 (1-350) containing Mn 2þ chelated to an unnatural amino acid assists in the characterization of the receptor-bound form of the chemokine.

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“…Over the past few years there has been an explosion in available GPCR structural information, which has provided a molecular understanding into ligand recognition 14 , receptor dynamics and activation 15 , and ligand-mediated biased signaling 16 . To date, three 5-HT receptors have been solved by X-ray crystallography: the 5-HT 1B 17,18 , 5-HT 2B 12 , and 5-HT 2C 19 receptors, all in complex with the VHD-inducing antimigraine drug ERG.…”

Section: Introductionmentioning

confidence: 99%

Structural determinants of 5-HT2B receptor activation and biased agonism

McCorvy

Wacker

Wang

et al. 2018

Nat Struct Mol Biol

136

122

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Serotonin receptors modulate a variety of physiological processes ranging from perception, cognition and emotion to vascular and smooth muscle contraction, platelet aggregation, gastrointestinal function and reproduction. Drugs that interact with serotonin receptors effectively treat diseases as diverse as migraine headaches, depression, and obesity. Here, we present four structures of a prototypical serotonin receptor—the human 5-HT2B receptor—in complex with chemically and pharmacologically diverse drugs, including methysergide, methylergonovine, lisuride, and LY266097. A detailed analysis of these structures complemented by comprehensive interrogation of signaling illuminates key structural determinants essential for activation. Additional structure-guided mutagenesis experiments revealed binding pocket residues essential for agonist-mediated biased signaling and β-arrestin2 translocation. Given the importance of serotonin receptors for a large number of therapeutic indications, insights derived from these studies should accelerate the design of safer and more effective medications.

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GPCR Dynamics: Structures in Motion

Cited by 645 publications

References 161 publications

Mechanism of allosteric regulation of β2-adrenergic receptor by cholesterol

Mechanism of allosteric regulation of β2-adrenergic receptor by cholesterol

Interaction of Monomeric Interleukin-8 with CXCR1 Mapped by Proton-Detected Fast MAS Solid-State NMR

Structural determinants of 5-HT2B receptor activation and biased agonism

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