Featured
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Article |
Promiscuous G-protein activation by the calcium-sensing receptor
Structures of the human calcium-sensing receptor can be bound into complex with G proteins from three different Gα subtypes while maintaining G-protein-binding specificity.
- Hao Zuo
- , Jinseo Park
- &Qing R. Fan
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Article |
Time-resolved cryo-EM of G-protein activation by a GPCR
Time-resolved cryo-EM is used to capture structural transitions during G-protein activation stimulatedby a G-protein-coupled receptor.
- Makaía M. Papasergi-Scott
- , Guillermo Pérez-Hernández
- &Georgios Skiniotis
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Article |
Allosteric modulation and G-protein selectivity of the Ca2+-sensing receptor
Cryo-electron microscopy structures of the human calcium-sensing receptor in complex with Gi and Gq proteins reveal how this receptor activates distinct G protein subtypes and how its function is modulated by a variety of ligands.
- Feng He
- , Cheng-Guo Wu
- &Georgios Skiniotis
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Article
| Open AccessAlternative splicing of latrophilin-3 controls synapse formation
Latrophilin-3 organizes synapses through a convergent dual-pathway mechanism in which Gαs signalling is activated and phase-separated postsynaptic protein scaffolds are recruited.
- Shuai Wang
- , Chelsea DeLeon
- &Thomas C. Südhof
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Article |
Ligand recognition and G-protein coupling of trace amine receptor TAAR1
TAAR1 has a rigid consensus binding motif that binds to endogenous trace amine stimuli as well as two extended binding pockets that accommodate diverse chemotypes.
- Zheng Xu
- , Lulu Guo
- &Zhenhua Shao
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Article
| Open AccessTail engagement of arrestin at the glucagon receptor
Structures of the glucagon receptor bound to β-arrestin 1 are reported, providing further information about the arrestin-mediated modulation of G protein-coupled receptors.
- Kun Chen
- , Chenhui Zhang
- &Beili Wu
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Article |
Structural basis of amine odorant perception by a mammal olfactory receptor
Cryo-electron microscopy structures of mouse trace amine-associated receptor 9 reveals structural motifs involved in odorant ligand recognition, including a unique disulfide bond linking the N terminus to extracellular loop 2.
- Lulu Guo
- , Jie Cheng
- &Jin-Peng Sun
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Article |
Structural basis for the tethered peptide activation of adhesion GPCRs
Adhesion GPCRs involved in cell and matrix interactions signal through a distinct self-cleavage,self-activation mechanism.
- Yu-Qi Ping
- , Peng Xiao
- &Jin-Peng Sun
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Article
| Open AccessStructural basis of tethered agonism of the adhesion GPCRs ADGRD1 and ADGRF1
Cryo-electron microscopy structures of the adhesion G protein-coupled receptors ADGRD1 and ADGRF1 provide insight into how these receptors are activated in an intrinsic manner through a ‘stalk’ region that acts as a tethered agonist.
- Xiangli Qu
- , Na Qiu
- &Beili Wu
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Article
| Open AccessActivation mechanism of the class D fungal GPCR dimer Ste2
Cryo-electron microscopy structures of ligand-free, agonist-bound and antagonist-bound Ste2 show that this class D1 Gprotein-coupled receptor has a distinct mechanism of activation compared with other receptor classes.
- Vaithish Velazhahan
- , Ning Ma
- &Christopher G. Tate
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Article |
G-protein activation by a metabotropic glutamate receptor
Cryo-electron microscopy structures show that metabotropic glutamate receptor 2 forms a dimer to which only one G protein is coupled, revealing the basis for asymmetric signal transduction.
- Alpay B. Seven
- , Ximena Barros-Álvarez
- &Georgios Skiniotis
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Article |
Asymmetric activation of the calcium-sensing receptor homodimer
Cryo-EM structures of human calcium-sensing receptor reveal intrinsic asymmetry in the receptor homodimer upon activation that isstabilized by calcimimetic drugs adopting distinct poses in the two protomers, priming one protomer for G-protein coupling.
- Yang Gao
- , Michael J. Robertson
- &Georgios Skiniotis
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Article |
Structures of Gi-bound metabotropic glutamate receptors mGlu2 and mGlu4
Cryo-electron microscopy structures of mGlu2 and mGlu4 bound to heterotrimeric Gi protein shed light on the molecular basis of asymmetric signal transduction by metabotropic glutamate receptors.
- Shuling Lin
- , Shuo Han
- &Beili Wu
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Article |
Structures of human mGlu2 and mGlu7 homo- and heterodimers
Cryo-electron microscopy structures of homo- and heterodimers of mGlu2 and mGlu7 provide insights into their dimerization modes and the subunit conformational changes that characterize the activation of these class C G-protein-coupled receptors.
- Juan Du
- , Dejian Wang
- &Qiang Zhao
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Article
| Open AccessStructural basis of GABAB receptor–Gi protein coupling
Cryo-electron microscopy structure of heterodimeric GABAB receptor in complex with Gi1 protein reveals that the mode of G-protein binding in this class-C G-protein-coupled receptor differs from that of other classes.
- Cangsong Shen
- , Chunyou Mao
- &Jianfeng Liu
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Article |
Structure of human GABAB receptor in an inactive state
The structure of the GABAB receptor in an inactive state reveals, amongst other features, a latch between the two subunits that locks the transmembrane domain interface, and the presence of large phospholipids that may modulate receptor function.
- Jinseo Park
- , Ziao Fu
- &Qing R. Fan
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Article |
Structures of metabotropic GABAB receptor
Cryo-electron microscopy structures of heterodimeric and homodimeric full-length GABAB receptors, combined with cellular signalling assays, shed light on the mechanisms that underpin signal transduction mediated by these receptors.
- Makaía M. Papasergi-Scott
- , Michael J. Robertson
- &Georgios Skiniotis
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Article |
Structural basis of the activation of a metabotropic GABA receptor
Cryo-electron microscopy structures of apo, agonist- and positive allosteric modulator-bound forms of the GB1–GB2 heterodimer of the metabotropic γ-aminobutyric acid (GABA) receptor shed light on the activation mechanism of this receptor.
- Hamidreza Shaye
- , Andrii Ishchenko
- &Vadim Cherezov
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Article |
Molecular basis of β-arrestin coupling to formoterol-bound β1-adrenoceptor
A cryo-electron microscopy structure of the β1-adrenoceptor coupled to β-arrestin 1 and activated by the biased agonist formoterol, as well as the crystal structure of a related formoterol-bound adrenoreceptor, provide insights into biased signalling in these systems.
- Yang Lee
- , Tony Warne
- &Christopher G. Tate
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Article |
Structure of the M2 muscarinic receptor–β-arrestin complex in a lipid nanodisc
A cryo-electron microscopy structure of β-arrestin 1 in complex with the M2 muscarinic receptor reconstituted in lipid nanodiscs is reported.
- Dean P. Staus
- , Hongli Hu
- &Georgios Skiniotis
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Article |
Structural basis of species-selective antagonist binding to the succinate receptor
High-resolution crystal structures of the rat succinate receptor SUCNR1 in an inactive confirmation, and the humanized rat SUCNR1 bound to an antagonist, provide insights into the structure of these receptors and the species selectivity of antagonist binding.
- Matthias Haffke
- , Dominique Fehlmann
- &Veli-Pekka Jaakola
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Letter |
Smoothened stimulation by membrane sterols drives Hedgehog pathway activity
The crystal structure of active mouse SMO in complex with the SAG21k agonist and a stabilizing intracellular binding nanobody reveals the structural basis of SMO regulation by PTCH1.
- Ishan Deshpande
- , Jiahao Liang
- &Aashish Manglik
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Article |
Conformational transitions of a neurotensin receptor1–Gi1complex
Cryo-electron microscopy structures of human neurotensin receptor1 in complex with Gi1 protein and the agonist JMV449 reveal a non-canonical state that may represent an intermediate form in G-protein activation.
- Hideaki E. Kato
- , Yan Zhang
- &Georgios Skiniotis
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Letter |
Structural basis of ligand recognition at the human MT1 melatonin receptor
The MT1 melatonin receptor differs markedly from 5-HT receptors and shows atypical ligand entry; its structure with various ligands sheds light on receptor specificity.
- Benjamin Stauch
- , Linda C. Johansson
- &Vadim Cherezov
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Letter |
XFEL structures of the human MT2 melatonin receptor reveal the basis of subtype selectivity
Structural and functional studies show that the MT2 melatonin receptor, unlike the MT1 receptor, contains an extracellular opening for ligand entry, shedding light on receptor subtype specificity.
- Linda C. Johansson
- , Benjamin Stauch
- &Vadim Cherezov
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Letter |
Cryo-EM structure of the serotonin 5-HT1B receptor coupled to heterotrimeric Go
The high-resolution structure of the serotonin 5-HT1B receptor in complex with the agonist donitriptan and a Go heterotrimer highlights features that may underlie the specificity of receptor–G-protein coupling and kinetics of signalling.
- Javier García-Nafría
- , Rony Nehmé
- &Christopher G. Tate
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Article |
Structure of the adenosine-bound human adenosine A1 receptor–Gi complex
The cryo-electron microscopy structure of the human adenosine A1 receptor in complex with adenosine and heterotrimeric Gi2 protein provides molecular insights into receptor and G-protein selectivity.
- Christopher J. Draper-Joyce
- , Maryam Khoshouei
- &Arthur Christopoulos
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Article |
Cryo-EM structure of human rhodopsin bound to an inhibitory G protein
The cryo-electron microscopy structure of human rhodopsin bound to the inhibitory Gi protein-coupled receptor provides insights into ligand–receptor–G-protein interactions.
- Yanyong Kang
- , Oleg Kuybeda
- &H. Eric Xu
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Letter |
Structural basis of ligand binding modes at the neuropeptide Y Y1 receptor
Crystal structures of the neuropeptide Y1 receptor in complex with two distinct antagonists combined with NMR, molecular docking and mutagenesis studies inform a proposed model for receptor–agonist binding.
- Zhenlin Yang
- , Shuo Han
- &Beili Wu
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Letter |
Structural insights into ligand recognition by the lysophosphatidic acid receptor LPA6
Determination of the crystal structure of the zebrafish LPA6 receptor shows that the lipid ligand binds to an unusual ligand-binding pocket in the receptor that is laterally accessible through the membrane.
- Reiya Taniguchi
- , Asuka Inoue
- &Osamu Nureki
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Article |
Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein
The structure of the GLP-1 receptor complexed with its ligand offers insight into the mechanism of class B G-protein-coupled receptor activation.
- Yan Zhang
- , Bingfa Sun
- &Georgios Skiniotis
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Article |
Activation mechanism of endothelin ETB receptor by endothelin-1
The X-ray crystal structures of human endothelin type B receptor in the ligand-free form and in complex with the endogenous agonist endothelin-1.
- Wataru Shihoya
- , Tomohiro Nishizawa
- &Tomoko Doi
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Article |
Structure-based discovery of opioid analgesics with reduced side effects
Computational docking to the the μ-opioid-receptor identifies PZM21, a novel selective biased agonist that generates substantial affective analgesia in mice without altering respiration or inducing drug reinforcement.
- Aashish Manglik
- , Henry Lin
- &Brian K. Shoichet
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Letter |
Diverse activation pathways in class A GPCRs converge near the G-protein-coupling region
A highly conserved rearrangement of residue contacts functions as a common step in the activation pathways of diverse G-protein-coupled receptors.
- A. J. Venkatakrishnan
- , Xavier Deupi
- &M. Madan Babu
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Letter |
Structure of the adenosine A2A receptor bound to an engineered G protein
An engineered G protein is used to bind to and stabilize the active conformation of the adenosine A2A receptor, enabling the acquisition of an X-ray crystal structure of this GPCR in an active state.
- Byron Carpenter
- , Rony Nehmé
- &Christopher G. Tate
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Article |
Structural basis of Smoothened regulation by its extracellular domains
Structural studies show that the activity of the G-protein-coupled receptor Smoothened is modulated by ligand-regulated interactions between its extracellular and transmembrane domains.
- Eamon F. X. Byrne
- , Ria Sircar
- &Christian Siebold
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Letter |
Allosteric coupling from G protein to the agonist-binding pocket in GPCRs
Here, pharmacological and biochemical evidence is provided that shows that G-protein coupling to the β2-adrenergic receptor stabilizes a ‘closed’ conformation of the G-protein-coupled receptor (GPCR) and that that the effects of the G protein on the ligand-binding site of the GPCR are observed even in the absence of a bound agonist.
- Brian T. DeVree
- , Jacob P. Mahoney
- &Roger K. Sunahara
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Letter |
Activation of the A2A adenosine G-protein-coupled receptor by conformational selection
The adenosine A2A receptor, a class A G-protein-coupled receptor, exists as an ensemble of two inactive and two active states in equilibrium and is activated by conformational selection rather than induced fit.
- Libin Ye
- , Ned Van Eps
- &R. Scott Prosser
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Letter |
Extra-helical binding site of a glucagon receptor antagonist
The X-ray crystal structure of the transmembrane portion of the human glucagon receptor, a class B G-protein-coupled receptor (GPCR), is solved in the presence of the antagonist MK-0893, with potential implications for the development of therapeutics that target other class B GPCRs.
- Ali Jazayeri
- , Andrew S. Doré
- &Fiona H. Marshall
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Letter |
The conformational signature of β-arrestin2 predicts its trafficking and signalling functions
A series of intramolecular fluorescent FlAsH BRET reporters is used to monitor conformational changes in β-arrestin2 following activation of seven G-protein-coupled receptors (GPCRs), showing that different GPCRs produce distinct β-arrestin2 conformational signatures that correlate with the stability of the receptor–arrestin complex and the role of β-arrestin2 in activating or dampening downstream signalling events, which explains how different GPCRs can use a common effector for different purposes.
- Mi-Hye Lee
- , Kathryn M. Appleton
- &Louis M. Luttrell
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Letter |
β-Arrestin biosensors reveal a rapid, receptor-dependent activation/deactivation cycle
A series of FRET-based β-arrestin2 biosensors are used to study the dynamics and conformational changes that occur when β-arrestin2 binds to and dissociates from the β2-adrenergic receptor in living cells; results show that after β-arrestin2 dissociates from the β2-adrenergic receptor, it stays at the cell membrane in an active conformation for a while, indicating that β-arrestin is able to signal in a G-protein-coupled receptor (GPCR)-free state.
- Susanne Nuber
- , Ulrike Zabel
- &Carsten Hoffmann
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Article |
Crystal structures of the M1 and M4 muscarinic acetylcholine receptors
X-ray crystal structures of the M1 and M4 muscarinic acetylcholine receptors, revealing differences in the orthosteric and allosteric binding sites that help to explain the subtype selectivity of drugs targeting this family of receptors.
- David M. Thal
- , Bingfa Sun
- &Arthur Christopoulos
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Article |
Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65
Yeast-based screening identifies the benzodiazepine drug lorazepam as a non-selective positive allosteric modulator of the G-protein-coupled receptor (GPCR) GPR68; homology modelling and molecular docking of 3.1 million molecules found a new compound, ‘ogerin’, as a potent GPR68 modulator, which suppressed recall in fear conditioning in wild-type mice, and the general method of combining physical and structure-based screening may lead to the discovery of selective ligands for other GPCRs.
- Xi-Ping Huang
- , Joel Karpiak
- &Bryan L. Roth
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Letter |
Conformational dynamics of a class C G-protein-coupled receptor
smFRET is used to probe the activation mechanism of two full-length mammalian glutamate receptors, revealing that the extracellular ligand-binding domains of these G-protein-coupled receptors interconvert between three confirmations (resting, activated and a short-lived intermediate state), and that the efficacy of an orthosteric agonist correlates with the degree of occupancy of the active state.
- Reza Vafabakhsh
- , Joshua Levitz
- &Ehud Y. Isacoff
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Article |
Structural insights into µ-opioid receptor activation
X-ray crystallography and molecular dynamics simulations of the μ-opioid receptor reveal the conformational changes in the extracellular and intracellular domains of this G-protein-coupled receptor that are associated with its activation.
- Weijiao Huang
- , Aashish Manglik
- &Brian K. Kobilka
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Letter |
Propagation of conformational changes during μ-opioid receptor activation
NMR spectroscopy reveals the conformational changes of the μ-opioid receptor that are associated with receptor activation, helping to explain why the allosteric coupling between the agonist-binding pocket and the cytoplasmic G-protein-coupling interface of this receptor is relatively weak.
- Rémy Sounier
- , Camille Mas
- &Sébastien Granier
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Article |
Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser
G protein-coupled receptors are a large family of signalling proteins that mediate cellular responses primarily via G proteins or arrestins, and they are targets of one-third of the current clinically used drugs; here, an active form of human rhodopsin bound to a pre-activated form of the mouse visual arrestin-1 is determined, revealing unique structural features that may constitute essential elements for arrestin-biased signalling.
- Yanyong Kang
- , X. Edward Zhou
- &H. Eric Xu
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Analysis |
Universal allosteric mechanism for Gα activation by GPCRs
There are ∼800 human GPCRs and 16 different Gα proteins; this study revealed the molecular details of Gα activation by GPCRs and suggests that a universal activation mechanism governs Gα activation—the details of this mechanism can explain how the GPCR–Gα system diversified rapidly, while conserving the allosteric activation mechanism.
- Tilman Flock
- , Charles N. J. Ravarani
- &M. Madan Babu
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Article |
Two disparate ligand-binding sites in the human P2Y1 receptor
Two X-ray crystal structures are presented of the human P2Y1 G-protein-coupled receptor, which is an important target for anti-thrombotic drugs; the structures unexpectedly reveal two ligand-binding sites.
- Dandan Zhang
- , Zhan-Guo Gao
- &Beili Wu
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Article |
Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain
An X-ray structure is presented for metabotropic glutamate receptor 5, a class C G-protein-coupled glutamate receptor linked to fragile X syndrome and neurological disorders; this study provides insights into the protein’s mechanism of action.
- Andrew S. Doré
- , Krzysztof Okrasa
- &Fiona H. Marshall
