Featured
-
-
Article
| Open AccessLipid nanodisc scaffold and size alter the structure of a pentameric ligand-gated ion channel
The authors show that lipid nanodiscs of different scaffold type and size alter the structure of the pentameric ligand-gated ion channel, ELIC. The results suggest that nanodisc selection is an important consideration for structural studies of membrane proteins.
- Vikram Dalal
- , Mark J. Arcario
- & Wayland W. L. Cheng
-
Article
| Open AccessElucidation of the structural basis for ligand binding and translocation in conserved insect odorant receptor co-receptors
Insects rely on olfaction for behavior control. Recent structural studies of receptors provide insight into ligand binding. Here, the authors identify dynamic binding mechanism to Orco, explaining its high selectivity with insights in compound screening.
- Jody Pacalon
- , Guillaume Audic
- & Jérémie Topin
-
Article
| Open AccessStructural insights into the allosteric inhibition of P2X4 receptors
Cryo-EM structures revealed how chemical compounds bind to and inhibit P2X4 receptors involved in neuropathic pain, potentially facilitating the design of drugs targeting P2X4 receptors.
- Cheng Shen
- , Yuqing Zhang
- & Motoyuki Hattori
-
Article
| Open AccessAsymmetric gating of a human hetero-pentameric glycine receptor
Despite essential roles in adult nervous systems, how heteromeric Cys-loop receptors work is unclear in the absence of an open state structure. Here, the authors report closed/open state structures and functional experiments, detailing an asymmetric gating mechanism driven by differing contributions from each subunit type.
- Xiaofen Liu
- & Weiwei Wang
-
Article
| Open AccessChronic cough relief by allosteric modulation of P2X3 without taste disturbance
P2X3 activation requires tightening the inner pocket of the head domain (IP-HD) following ATP binding. Here the authors demonstrate that targeting the IP-HD with allosteric small molecules presents a potential strategy for the development of therapeutics for refractory chronic cough without taste abnormalities.
- Chang-Run Guo
- , Zhong-Zhe Zhang
- & Ye Yu
-
Article
| Open AccessStructural interplay of anesthetics and paralytics on muscle nicotinic receptors
Here the authors use a structural approach to reveal how neuromuscular blockers and a general anesthetic antagonize the muscle-type nicotinic receptor through competitive and allosteric mechanisms.
- Umang Goswami
- , Md Mahfuzur Rahman
- & Ryan E. Hibbs
-
Article
| Open AccessDerepression may masquerade as activation in ligand-gated ion channels
Ligand-gated ion channels are activated/opened by agonists. Tessier et al. show that agonists can inhibit the inhibition of intrinsic basal activity, and thus that activation may instead be the manifestation of a derepression mechanism.
- Christian J. G. Tessier
- , Johnathon R. Emlaw
- & Corrie J. B. daCosta
-
Article
| Open AccessModulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics
AMPA receptors associated with TARP subunits enable the development of selective AMPA receptor drugs. Here, the authors provide cryo-EM structures of receptors bound to three TARP-γ8 selective drugs, and reveal bifunctionality of one ligand.
- Danyang Zhang
- , Remigijus Lape
- & Ingo H. Greger
-
Article
| Open AccessConformational transitions and allosteric modulation in a heteromeric glycine receptor
Glycine receptors (GlyR) are a critical postsynaptic component of spinal neurons. Here, the auhtors present cryo-EM structures of a heteromeric GlyR in the presence of an antagonist, agonist and agonist with a positive allosteric modulator.
- Eric Gibbs
- , Emily Klemm
- & Sudha Chakrapani
-
Article
| Open AccessOpen-channel structure of a pentameric ligand-gated ion channel reveals a mechanism of leaflet-specific phospholipid modulation
Pentameric ligand-gated ion channels are modulated by anionic phospholipids. Here, by capturing an open-channel conformation of ELIC, the authors demonstrate the structural details of channel activation and a leaflet-specific mechanism for modulation by phosphatidylglycerol.
- John T. Petroff II
- , Noah M. Dietzen
- & Wayland W. L. Cheng
-
Article
| Open AccessConformational motions and ligand-binding underlying gating and regulation in IP3R channel
Here authors report cryo-EM structures of IP3R1 which provide atomic details of IP3, Ca2+ and ATP binding. Molecular motions of key domains and sidechains were found to regulate ligand binding and gating, which are validated by functional assays.
- Guizhen Fan
- , Mariah R. Baker
- & Irina I. Serysheva
-
Article
| Open AccessStructural basis for the activation of the lipid scramblase TMEM16F
TMEM16F is a dual ion channel and lipid scramblase that is involved in blood coagulation and cell fusion. Here, authors elucidate how the protein is activated by Ca2+ to accomplish both functions in a single protein conformation.
- Melanie Arndt
- , Carolina Alvadia
- & Raimund Dutzler
-
Article
| Open AccessStructural basis for cannabinoid-induced potentiation of alpha1-glycine receptors in lipid nanodiscs
Glycine receptors (GlyRs) mediate motor control and pain perception. Here, Kumar et al. present structures of GlyR bound to Δ9 -tetrahydrocannabinol (THC) using cryo-electron microscopy, providing insight into the therapeutic effects of cannabinoids.
- Arvind Kumar
- , Kayla Kindig
- & Sudha Chakrapani
-
Article
| Open AccessThe molecular mechanism of snake short-chain α-neurotoxin binding to muscle-type nicotinic acetylcholine receptors
Bites by elapid snakes can result in life-threatening paralysis caused by α-neurotoxins blocking the neuromuscular nicotinic acetylcholine receptor. Here, the authors determine the cryo-EM structure of this receptor in complex with a short-chain α-neurotoxin.
- Mieke Nys
- , Eleftherios Zarkadas
- & Chris Ulens
-
Article
| Open AccessStructures of highly flexible intracellular domain of human α7 nicotinic acetylcholine receptor
The intracellular domain (ICD) of Cys-loop receptors mediates many of their functions, but no complete structure of a Cys-loop receptor ICD is available to date. Here, the authors combine NMR and ESR spectroscopy to determine the full-length ICD structures of the human α7 nicotinic acetylcholine receptor (α7nAChR).
- Vasyl Bondarenko
- , Marta M. Wells
- & Pei Tang
-
Article
| Open AccessMechanisms underlying TARP modulation of the GluA1/2-γ8 AMPA receptor
AMPA glutamate receptors, mediate the majority of excitatory signaling in the brain. Here the authors show how the auxiliary subunit TARP-γ8 shapes gating kinetics, ion conductance and rectification properties of the heteromeric GluA1/2 AMPA receptor.
- Beatriz Herguedas
- , Bianka K. Kohegyi
- & Ingo H. Greger
-
Article
| Open AccessStructural determinants and regulation of spontaneous activity in GABAA receptors
GABAA receptors (GABAARs) cause inhibition in the brain by functioning as heteropentamers formed from multiple subunit types. Here, the authors demonstrate that receptors incorporating β3 subunits can spontaneously gate, which is modulated by protein kinases and neurosteroids to affect tonic inhibition.
- Craig A. Sexton
- , Reka Penzinger
- & Trevor G. Smart
-
Article
| Open AccessLigand-directed two-step labeling to quantify neuronal glutamate receptor trafficking
The analysis of AMPA-type glutamate receptor (AMPAR) trafficking is essential for understanding molecular mechanisms of learning and memory, but the analytical tools are currently limited. Here, the authors report a method that combines affinity-based receptor labeling and bioorthogonal click chemistry to quantify AMPAR distribution and trafficking under physiological conditions.
- Kento Ojima
- , Kazuki Shiraiwa
- & Shigeki Kiyonaka
-
Article
| Open AccessThe desensitization pathway of GABAA receptors, one subunit at a time
GABAA receptors mediate most inhibitory synaptic transmission in the brain. Here authors used concatemeric α1β2γ2 GABAA receptors to introduce gain-of-desensitization mutations one subunit at a time, revealing non-concerted rearrangements with a key contribution of the γ2 subunit during desensitization.
- Marc Gielen
- , Nathalie Barilone
- & Pierre-Jean Corringer
-
Article
| Open AccessMechanisms of activation and desensitization of full-length glycine receptor in lipid nanodiscs
Glycinergic synapses play a central role in motor control and pain processing in the central nervous system. Here, authors present cryo-EM structures of the full-length glycine receptors (GlyRs) reconstituted into lipid nanodiscs in the unliganded, glycine-bound and allosteric modulator-bound conformations and reveal global conformational changes underlying GlyR channel gating and modulation.
- Arvind Kumar
- , Sandip Basak
- & Sudha Chakrapani
-
Article
| Open AccessStructural basis of subtype-selective competitive antagonism for GluN2C/2D-containing NMDA receptors
Selectively inhibiting N-Methyl-D-aspartate receptors (NMDARs) containing the GluN2C/2D subunits has been challenging. Here, using electrophysiology and X-ray crystallography, authors show that compounds UBP791 and UBP1700 show over 40- and 50-fold selectivity for GluN2C/2D compared to GluN2A.
- Jue Xiang Wang
- , Mark W. Irvine
- & Hiro Furukawa
-
Article
| Open AccessStructural insights into the competitive inhibition of the ATP-gated P2X receptor channel
P2X receptors are nonselective cation channels that are gated by extracellular ATP. Here the authors present the crystal structure of chicken P2X7 with its bound competitive antagonist TNP-ATP and give mechanistic insights into TNP-ATP dependent inhibition through further computational analysis and electrophysiology measurements.
- Go Kasuya
- , Toshiaki Yamaura
- & Osamu Nureki
-
Article
| Open AccessNMDA receptors are selectively partitioned into complexes and supercomplexes during synapse maturation
NMDARs and MAGUK proteins are capable of forming higher-order protein assemblies, however their organisation in the intact brain is unclear. Here, Frank et al. identify mouse and human supercomplexes and discover their mechanism of assembly using genetic tagging and affinity purification.
- René A. W. Frank
- , Noboru H. Komiyama
- & Seth G. N. Grant
-
Article
| Open AccessStructural correlates of affinity in fetal versus adult endplate nicotinic receptors
Adult and fetal nicotinic acetylcholine receptors (AChRs) have different functional requirements and affinity for ACh. Here, the authors use molecular dynamics and electrophysiology to investigate this affinity, and identify four amino acids that when swapped exchange function between adult and fetal AChRs.
- Tapan Kumar Nayak
- , Srirupa Chakraborty
- & Anthony Auerbach
-
Article |
Structural basis for potentiation by alcohols and anaesthetics in a ligand-gated ion channel
Alcohols and anaesthetics exert their effects by potentiating ligand-gated ion channels. Here, the authors determine crystal structures of a bacterial ligand-gated ion channel in the presence of alcohols and anaesthetics, and describe a structural mechanism for stabilization of the open form of the channel.
- Ludovic Sauguet
- , Rebecca J. Howard
- & Marc Delarue
-
Article |
Robust photoregulation of GABAA receptors by allosteric modulation with a propofol analogue
The design of chemical photoswitches could potentially lead to the development of novel therapeutics that regulates neurotransmission. In this study, a light-sensitive modified derivative of propofol is shown to activate GABAA receptors in Xenopusoocytes, rat ganglion cells and mouse cerebellar slices.
- Lan Yue
- , Michal Pawlowski
- & David R. Pepperberg
-
Article
| Open AccessStructure of the pentameric ligand-gated ion channel ELIC cocrystallized with its competitive antagonist acetylcholine
The pentameric ligand gated ion channel fromErwinia chrysanthemi(ELIC) is similar in structure to the nicotinic acetylcholine receptor, a member of the Cys-loop receptor family. This study reports the crystal structure of ELIC bound to acetylcholine and shows that acetylcholine is a competitive antagonist of ELIC.
- Jianjun Pan
- , Qiang Chen
- & Pei Tang
-
Article |
NMDA receptor activation requires remodelling of intersubunit contacts within ligand-binding heterodimers
In non-NMDA glutamate receptors, intersubunit contacts within agonist binding domains affect functional desensitization. Now, NMDA receptor activation, but not desensitization, is shown to involve rearrangements at the heterodimer interface, suggesting that the intersubunit contacts of NMDA and non-NMDA receptors may have distinct functional roles.
- William F. Borschel
- , Swetha E. Murthy
- & Gabriela K. Popescu
-
Article |
Ligand-specific deactivation time course of GluN1/GluN2D NMDA receptors
N-methyl-D-aspartate receptors mediate excitatory synaptic transmission, and those containing GluN2D subunits have an unusually long deactivation time. Vance et al. show that the conformational variability of the ligand-binding domain and the structure of the activating ligand influence deactivation time.
- Katie M. Vance
- , Noriko Simorowski
- & Hiro Furukawa
-
Article |
A subunit-selective potentiator of NR2C- and NR2D-containing NMDA receptors
NMDA receptors are complexes of NR1 and NR2 subunits that mediate excitatory synaptic transmission and have roles in neurological disorders. Here, a subunit-selective potentiator of NMDA receptors is identified, which may allow the evaluation of the functional roles of individual NMDA receptor subunits.
- Praseeda Mullasseril
- , Kasper B. Hansen
- & Stephen F. Traynelis
-
Article
| Open AccessPore-opening mechanism in trimeric P2X receptor channels
A recent X-ray structure revealed the closed state of a P2X receptor ion channel. Here, Li and colleagues probe the structural rearrangements that take place during channel opening by measuring the effects of covalent modification of engineered cysteines.
- Mufeng Li
- , Toshimitsu Kawate
- & Kenton J. Swartz