A Conserved Proline Hinge Mediates Helix Dynamics and Activation of Rhodopsin

Pope, Andreyah; Sánchez-Reyes, Omar B.; South, Kieron; Zaitseva, Ekaterina; Ziliox, Martine; Vogel, Reiner; Reeves, Philip J.; Smith, Steven O.

doi:10.1016/j.str.2020.05.004

Cited by 16 publications

(25 citation statements)

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“…This predisposes this region to act as a flexible hinge that would allow the outward rotation of the intracellular end of H6 [17,43] (Figure 2D). Recent NMR studies argue that a key function of the TM core is to constrain this hinge in an inactive receptor and to allow it to sample a range of conformational states upon activation [38] (see below).…”

Section: Prolines Can Function As Switches and Hingesmentioning

confidence: 99%

“…From these studies, a mechanistic picture of TM signal transduction has emerged in which ligand binding triggers conformational changes within the TM core that are coupled to changes in the conserved motifs on the intracellular side of the receptor. Recent NMR studies build on this picture to address how ligand binding modulates local receptor dynamics to produce the observed global conformational changes between inactive and active receptors [36][37][38][39][40][41].…”

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confidence: 99%

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Deconstructing the transmembrane core of class A G protein–coupled receptors

Smith

2021

Trends in Biochemical Sciences

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Class A G protein-coupled receptors have evolved to recognize ligands ranging from small-molecule odorants to proteins. Although they are among the most diverse membrane receptors in eukaryotic organisms, they possess a highly conserved core within their seven-transmembrane helix framework. The conservation of the transmembrane core has led to the idea of a common mechanism by which ligand binding is coupled to the outward rotation of helix H6, the hallmark of an active receptor. Nevertheless, there is still no consensus on the mechanism of coupling or on the roles of specific residues within the core. Recent insights from crystallography and NMR spectroscopy provide a way to decompose the core into its essential structural and functional elements that shed new light on this important region.A common transmembrane core in class A G protein-coupled receptors G protein-coupled receptors (GPCRs; see Glossary) control the ability to sense the external environment by acting as receptors for vision, smell, and taste [1][2][3]. They also exert a strong influence over our internal environment through modulation of neuronal responses and control of key physiological processes. Correspondingly, they have emerged as a major target for pharmaceuticals [4][5][6]. In humans, there are five main GPCR classes: rhodopsin (class A), secretin (class B1), adhesion (class B2), glutamate (class C), and Frizzled and Taste2 (class F) [7] (see also https://gpcrdb.org). The only significant sequence identity between the different GPCR classes is between the B1 and B2 receptor classes. However, a seven-transmembrane (TM) helix architecture and the ability to bind and activate G proteins are common features throughout all classes [8,9]. Class A is the largest, most extensively studied GPCR family in humans with >800 members [7]. This class of receptors is defined by a conserved set of motifs within the TM helices that couple extracellular ligand binding to the opening of a G protein binding site on the intracellular side of the receptor [10,11] (Figure 1). Within the class A receptors, there are 11 subfamilies that exhibit unique sequence and structural differences associated with their ability to recognize distinct types of ligands (https://gpcrdb.org). Well-known class A subfamilies include the visual, olfactory, aminergic, and peptide hormone receptors.The seven-TM bundle can conceptually be divided into three regions [12,13] (Figure 1A). The extracellular ligand-binding region, which is formed by the N terminus, extracellular loops, and extracellular ends of the TM helices, has evolved to recognize a diverse range of signals. The intracellular region, which is formed by the C terminus, intracellular loops, and intracellular ends of the TM helices, is the site of binding of the heterotrimeric G proteins, GPCR kinases, and arrestins [2]. The TM core of class A GPCRs can be seen as the transducer to convert an extracellular signal into one or more intracellular signals. It spans roughly two helical turns in the middle of the TM domain and ...

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Section: Prolines Can Function As Switches and Hingesmentioning

confidence: 99%

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confidence: 99%

Deconstructing the transmembrane core of class A G protein–coupled receptors

Smith

2021

Trends in Biochemical Sciences

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“…FTIR has been widely used to address the activation process of rhodopsin [ 35 , 204 , 295 , 296 , 297 , 298 , 299 , 300 , 301 , 302 , 303 ], mostly taking advantage of the sensitivity of C=O vibrations to the protonation state of aspartate and glutamate residues and conformational changes [ 295 , 298 ]. For instance, FTIR in combination with UV–VIS has been used to develop a thermodynamic model of rhodopsin activation including the short-lived intermediates [ 298 ] and to investigate changes occurring in the intracellular side of the receptor upon binding of the Gα C-terminal peptide [ 35 ].…”

Section: A Receptor’s Perspectivementioning

confidence: 99%

Capturing Peptide–GPCR Interactions and Their Dynamics

Kaiser

Coin

2020

Molecules

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Many biological functions of peptides are mediated through G protein-coupled receptors (GPCRs). Upon ligand binding, GPCRs undergo conformational changes that facilitate the binding and activation of multiple effectors. GPCRs regulate nearly all physiological processes and are a favorite pharmacological target. In particular, drugs are sought after that elicit the recruitment of selected effectors only (biased ligands). Understanding how ligands bind to GPCRs and which conformational changes they induce is a fundamental step toward the development of more efficient and specific drugs. Moreover, it is emerging that the dynamic of the ligand–receptor interaction contributes to the specificity of both ligand recognition and effector recruitment, an aspect that is missing in structural snapshots from crystallography. We describe here biochemical and biophysical techniques to address ligand–receptor interactions in their structural and dynamic aspects, which include mutagenesis, crosslinking, spectroscopic techniques, and mass-spectrometry profiling. With a main focus on peptide receptors, we present methods to unveil the ligand–receptor contact interface and methods that address conformational changes both in the ligand and the GPCR. The presented studies highlight a wide structural heterogeneity among peptide receptors, reveal distinct structural changes occurring during ligand binding and a surprisingly high dynamics of the ligand–GPCR complexes.

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“…Whereas these structures provide a static picture of the different conformations of the receptor in individual states, the dynamics of the structural transitions between such states can be studied in detail by spectroscopic tools [ 19 ], in particular by NMR spectroscopy [ 9 ]. Using NMR spectroscopy in a solution [ 20 , 21 , 22 , 23 ] and in the solid state [ 24 , 25 ], the dynamics of the conformational transitions in GPCRs have been characterized in atomistic detail. Receptor activation is characterized by a seesaw-like swing of transmembrane Helices 6 (TM6) and 7 (TM7), by which the extra- and intracellular ends of the helices are moved in the opposite direction [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…Receptor activation is characterized by a seesaw-like swing of transmembrane Helices 6 (TM6) and 7 (TM7), by which the extra- and intracellular ends of the helices are moved in the opposite direction [ 11 ]. For the function of GPCRs, a number of activation switches have been identified, which represent well-conserved amino acid residues that change their conformation upon ligand binding, thereby inducing the dynamic reorientation of the TM segments of the molecule [ 25 ]. Molecular switches are part of an activation network of interacting residues that undergo restructuring upon activation [ 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

The Dynamics of the Neuropeptide Y Receptor Type 1 Investigated by Solid-State NMR and Molecular Dynamics Simulation

et al. 2020

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We report data on the structural dynamics of the neuropeptide Y (NPY) G-protein-coupled receptor (GPCR) type 1 (Y1R), a typical representative of class A peptide ligand GPCRs, using a combination of solid-state NMR and molecular dynamics (MD) simulation. First, the equilibrium dynamics of Y1R were studied using 15N-NMR and quantitative determination of 1H-13C order parameters through the measurement of dipolar couplings in separated-local-field NMR experiments. Order parameters reporting the amplitudes of the molecular motions of the C-H bond vectors of Y1R in DMPC membranes are 0.57 for the Cα sites and lower in the side chains (0.37 for the CH2 and 0.18 for the CH3 groups). Different NMR excitation schemes identify relatively rigid and also dynamic segments of the molecule. In monounsaturated membranes composed of longer lipid chains, Y1R is more rigid, attributed to a higher hydrophobic thickness of the lipid membrane. The presence of an antagonist or NPY has little influence on the amplitude of motions, whereas the addition of agonist and arrestin led to a pronounced rigidization. To investigate Y1R dynamics with site resolution, we conducted extensive all-atom MD simulations of the apo and antagonist-bound state. In each state, three replicas with a length of 20 μs (with one exception, where the trajectory length was 10 μs) were conducted. In these simulations, order parameters of each residue were determined and showed high values in the transmembrane helices, whereas the loops and termini exhibit much lower order. The extracellular helix segments undergo larger amplitude motions than their intracellular counterparts, whereas the opposite is observed for the loops, Helix 8, and termini. Only minor differences in order were observed between the apo and antagonist-bound state, whereas the time scale of the motions is shorter for the apo state. Although these relatively fast motions occurring with correlation times of ns up to a few µs have no direct relevance for receptor activation, it is believed that they represent the prerequisite for larger conformational transitions in proteins.

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A Conserved Proline Hinge Mediates Helix Dynamics and Activation of Rhodopsin

Cited by 16 publications

References 63 publications

Deconstructing the transmembrane core of class A G protein–coupled receptors

Deconstructing the transmembrane core of class A G protein–coupled receptors

Capturing Peptide–GPCR Interactions and Their Dynamics

The Dynamics of the Neuropeptide Y Receptor Type 1 Investigated by Solid-State NMR and Molecular Dynamics Simulation

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