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| Open AccessMolecular basis of Mg2+ permeation through the human mitochondrial Mrs2 channel
Mrs2 is a mitochondrial Mg2+ channel that is essential for metabolic function. Here, the authors present cryo-EM structures of human Mrs2 revealing symmetrical pentameric assembly and how Mrs2 permeates Mg2+.
- Ming Li
- , Yang Li
- & Yuequan Shen
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Article
| Open AccessSubunit gating resulting from individual protonation events in Kir2 channels
Here, authors introduced negative charges in the transmembrane helices in Kir2.2 channels generating pH-dependent sub-conductances. Molecular dynamics simulations show how protonation results in step-wise alterations of ion pooling and hence conductance, appearing as gated substates.
- Grigory Maksaev
- , Michael Bründl-Jirout
- & Colin G. Nichols
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Article
| Open AccessStructural basis of CXC chemokine receptor 1 ligand binding and activation
Chemokines are small proteins secreted at sites of injury. Here, the authors describe the structure of the chemokine receptor CXCR1 bound to chemokine CXCL8, solved by cryo-EM. The model helps explain the ligand preferences of this receptor.
- Naito Ishimoto
- , Jae-Hyun Park
- & Sam-Yong Park
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Article
| Open AccessEstablishing mammalian GLUT kinetics and lipid composition influences in a reconstituted-liposome system
Transport assays using purified glucose transporters (GLUTs) have proven to be difficult to implement, hampering deeper mechanistic insights. Here the authors have optimized a transport assay in liposomes that will provide insight to study other membrane transport proteins.
- Albert Suades
- , Aziz Qureshi
- & David Drew
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Article
| Open AccessProfiling of basal and ligand-dependent GPCR activities by means of a polyvalent cell-based high-throughput platform
Interrogating the dynamic and functionally diverse signaling of GPCRs requires comprehensive cellular tools. Here Zeghal et al. develop Tango-Trio, a screening platform capable of profiling basal and drug-activated activities at hundreds of GPCRs.
- Manel Zeghal
- , Geneviève Laroche
- & Patrick M. Giguère
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Article
| Open AccessStructure of human CALHM1 reveals key locations for channel regulation and blockade by ruthenium red
The voltage-dependent CALHM1 channel is critical in neuromodulation and gustatory signaling. The authors present cryo-EM structures of human CALHM1 in apo- and blocked-states. They explore effects of lipid binding on channel structure and activity.
- Johanna L. Syrjänen
- , Max Epstein
- & Hiro Furukawa
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Article
| Open AccessTRPV4-Rho GTPase complex structures reveal mechanisms of gating and disease
Despite TRPV4’s medical importance, the mechanisms of ligand-mediated channel gating and its regulation by Rho GTPase are unclear. Here, the authors report the structures of TRPV4 in complex with RhoA and ligands, offering atomic-level insights into their functions.
- Do Hoon Kwon
- , Feng Zhang
- & Seok-Yong Lee
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Article
| Open AccessCyclic di-AMP traps proton-coupled K+ transporters of the KUP family in an inward-occluded conformation
Second messengers regulate a broad spectrum of processes in bacteria. Here, authors characterize how the second messenger cyclic di-AMP inhibits the potassium transporter KimA using cryo-EM, molecular dynamics simulations and functional assays.
- Michael F. Fuss
- , Jan-Philip Wieferig
- & Inga Hänelt
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Article
| Open AccessCannabidiol inhibits Nav channels through two distinct binding sites
Cannabidiol (CBD), the nonpsychoactive component in cannabis, is an effective treatment for epilepsy and pain. Here, authors explored the mode of action of CBD on hNav1.7 channels through two distinct binding sites, suggesting a direct stabilization of the inactivated state of channels.
- Jian Huang
- , Xiao Fan
- & Nieng Yan
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Article
| Open AccessThe inhibition mechanism of the SUR2A-containing KATP channel by a regulatory helix
Cardiac KATP channels consisting of SUR2A are poorly activated by Mg-ADP compared to other subtypes. Here, the authors present structures of SUR2A and SUR2B, uncovering a regulatory helix that inhibits SUR2A activation.
- Dian Ding
- , Tianyi Hou
- & Lei Chen
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Article
| Open AccessSubstrate binding-induced conformational transitions in the omega-3 fatty acid transporter MFSD2A
Molecular mechanisms of MFSD2A-mediated lysolipid transport into the brain has been elusive. Here, using molecular dynamics, the authors uncover how initial stages of transport cycle are enabled by substrate-induced conformational changes in MFSD2A.
- Shana Bergman
- , Rosemary J. Cater
- & George Khelashvili
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Article
| Open AccessStructural mechanism of intracellular autoregulation of zinc uptake in ZIP transporters
Zinc uptake and regulation are vital in all life forms. Here, authors describe a dimer of a ZIP-family zinc transporter in an inward-facing, inhibited conformation. A built-in zinc sensor is proposed to sense the intracellular zinc content to autoregulate zinc uptake across membranes.
- Changxu Pang
- , Jin Chai
- & Qun Liu
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Article
| Open AccessNative American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain
Drugs that rescue function of episodic ataxia 1 (EA1) mutant potassium channels are lacking. Here, Manville et al identify and describe the molecular basis for Native American botanical ataxia remedies that directly rescue EA1 mutant channels.
- Rían W. Manville
- , J. Alfredo Freites
- & Geoffrey W. Abbott
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Article
| Open AccessStructural mapping of Nav1.7 antagonists
Voltage-gated sodium (Nav) channels are targeted by various clinically applied and investigational drugs. Here cryo-EM structures of Nav1.7 bound to 7 compounds with diverse chemical skeletons reveal the structural basis of action of these drugs and provide a 3D structural map for drug binding sites on Nav channels.
- Qiurong Wu
- , Jian Huang
- & Nieng Yan
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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
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Article
| Open AccessThe AE4 transporter mediates kidney acid-base sensing
Maintaining systemic acid-base balance is a central task of the kidneys, but it is still undetermined how acid-base alterations are perceived by the kidney. Here, the authors show that the solute transporter AE4 in β-intercalated cells is an essential part of the renal acid-base sensing mechanism
- H. Vitzthum
- , M. Koch
- & H. Ehmke
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Article
| Open AccessAsymmetric pendrin homodimer reveals its molecular mechanism as anion exchanger
Pendrin SLC26A4 plays an important role for anion balance. Here, authors resolve cryo-EM structures of pendrin performing co-incident uptake and secretion of anions, providing a structural basis of this anion exchange mechanism.
- Qianying Liu
- , Xiang Zhang
- & Zhenguo Chen
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Article
| Open AccessAnt venoms contain vertebrate-selective pain-causing sodium channel toxins
Stings of certain ant species can cause intense, long-lasting nociception. Here, authors show that the major contributors of these symptoms are vertebrate-selective defensive venom peptides which modulate the activity of voltage-gated sodium channels.
- Samuel D. Robinson
- , Jennifer R. Deuis
- & Irina Vetter
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Article
| Open AccessMolecular mechanism of hyperactivation conferred by a truncation of TRPA1
A drastic TRPA1 mutant was identified in patients with CRAMPT syndrome, but it has not been functionally characterized. Here, the authors find this mutant confers gain-of-function by co-assembling with wild type protein to form hyperactive channels.
- Avnika Bali
- , Samantha P. Schaefer
- & Candice E. Paulsen
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Article
| Open AccessVesicular glutamate transporters are H+-anion exchangers that operate at variable stoichiometry
In glutamatergic neurons, synaptic vesicles contain glutamate, but not aspartate. Here, the authors show that vesicular glutamate transporters are H+/anion exchangers that attain high selectivity for glutamate via variable transport coupling.
- Bettina Kolen
- , Bart Borghans
- & Christoph Fahlke
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Article
| Open AccessTwo single-point mutations in Ankyrin Repeat one drastically change the threshold temperature of TRPV1
TRPV1 is a noxious heat sensor. Here, authors showed that tailed amphibians express TRPV1 with a reduced heat-activation threshold by substitution of two amino acids in the N-terminal region to contribute to cool-habitat selection.
- Shogo Hori
- , Michihiro Tateyama
- & Osamu Saitoh
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Article
| Open AccessStructural mechanisms of TRPM7 activation and inhibition
Authors present the structural mechanisms of TRPM7 spontaneous and agonist-induced opening and inhibition by potent and selective antagonists.
- Kirill D. Nadezhdin
- , Leonor Correia
- & Alexander I. Sobolevsky
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Article
| Open AccessLipid flipping in the omega-3 fatty-acid transporter
Lipid flipping across membrane leaflets are vital yet enigmatic biological processes. Here, five cryo-EM structures provide snapshots to delineate a mechanism of omega-3 fatty acid flipping across the blood brain barrier.
- Chi Nguyen
- , Hsiang-Ting Lei
- & Tamir Gonen
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Article
| Open AccessMolecular determinants of inhibition of UCP1-mediated respiratory uncoupling
Combining molecular dynamic simulations with in vivo functional assays, Gagelin et al. identified unique molecular features of the mitochondrial carrier uncoupling protein 1 that are crucial to its inhibition by nucleotides
- Antoine Gagelin
- , Corentin Largeau
- & Bruno Miroux
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Article
| Open AccessPain-causing stinging nettle toxins target TMEM233 to modulate NaV1.7 function
Voltage-gated sodium channels function as multiprotein signaling complexes. Here, authors show that the dispanin TMEM233 is essential for activity of stinging nettle toxins and that co-expression of TMEM233 modulates the gating properties of NaV1.7.
- Sina Jami
- , Jennifer R. Deuis
- & Irina Vetter
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Article
| Open AccessParkinson’s disease-associated ATP13A2/PARK9 functions as a lysosomal H+,K+-ATPase
Mutations in the human ATP13A2, a lysosomal ATPase, is associated with pathogenesis of Parkinson’s disease. Here, the authors show that ATP13A2 functions as H + /K + transporting protein, preventing lysosomal alkalinization and α-synuclein accumulation.
- Takuto Fujii
- , Shushi Nagamori
- & Hideki Sakai
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Article
| Open AccessCentral cavity dehydration as a gating mechanism of potassium channels
The hydrophobic gating is believed to function in various ion channels. Here, the authors use MD simulations to assess how dewetting of the channel pore modulates the function and conformational transition of the potassium channels.
- Ruo-Xu Gu
- & Bert L. de Groot
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Article
| Open AccessStructure and mechanism of the alkane-oxidizing enzyme AlkB
Alkane monooxygenase (AlkB) plays a key role in the global carbon cycle and remediation of oil spills. Here, the authors report the cryo-EM structure of AlkB to provide insight into the catalytic mechanism and substrate selectivity.
- Xue Guo
- , Jianxiu Zhang
- & Liang Feng
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Article
| Open AccessA cationic motif upstream Engrailed2 homeodomain controls cell internalization through selective interaction with heparan sulfates
Here, the authors show that cell internalization of Engrailed2 not only relies on its homeodomain, but also involves a cationic region which interacts selectively with cell surface heparan sulfates.
- Sébastien Cardon
- , Yadira P. Hervis
- & Sandrine Sagan
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Article
| Open AccessConformational cycle of human polyamine transporter ATP13A2
ATP13A2 is a lysosomal polyamine transporter, mutated in several diseases including juvenile-onset Parkinson’s disease. Here, the authors report structures of human ATP13A2 in six distinct intermediate states, illustrating most of its conformational cycle.
- Jianqiang Mu
- , Chenyang Xue
- & Zhongmin Liu
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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
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Article
| Open AccessThe structural basis of the pH-homeostasis mediated by the Cl−/HCO3− exchanger, AE2
Cells maintain a narrow physiological pH by exchanging intracellular bicarbonate for extracellular chloride. Here, authors determine the cryo-EM structures of human anion exchanger 2 (AE2) in five major operating states and one transitional state, to collectively demonstrate the process of pH-balancing.
- Qing Zhang
- , Liyan Jian
- & Yu Cao
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Article
| Open AccessMutation in glutamate transporter homologue GltTk provides insights into pathologic mechanism of episodic ataxia 6
Episodic ataxias (EAs) are rare neurological conditions that cause motor impairment. Here the authors investigated the molecular mechanism of such a pathological condition caused by a mutation of a conserved proline into arginine residue.
- Emanuela Colucci
- , Zaid R. Anshari
- & Albert Guskov
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Article
| Open AccessStructural insights into the mechanism of leptin receptor activation
Leptin is a master regulator of body weight and energy homeostasis that is dysregulated in obesity. Here, authors determined the cryo-EM structure of the activated Leptin receptor complex, revealing insights into the mechanism of Leptin signaling
- Robert A. Saxton
- , Nathanael A. Caveney
- & K. Christopher Garcia
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Article
| Open AccessStructural basis of the substrate recognition and inhibition mechanism of Plasmodium falciparum nucleoside transporter PfENT1
PfENT1 is a promising antimalarial drug target. Here, authors report cryo-EM structures of PfENT1 that, together with biochemical work, suggests PfENT1 is an inosine transporter and describe the inhibitory mechanism of the endofacial inhibitor, GSK4.
- Chen Wang
- , Leiye Yu
- & Dong Deng
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Article
| Open AccessStructural insights into the human niacin receptor HCA2-Gi signalling complex
Hydroxyl-carboxylic acid receptor 2 (HCA2) functions as a high-affinity receptor for nicotinic acid (vitamin B3). Here, authors report the cryo-EM structure of the HCA2-Gi complex with the agonist MK-6892 and inactive state crystal structures of mutation stabilized HCA2, to describe the mechanism of HCA2 signaling.
- Yang Yang
- , Hye Jin Kang
- & Zhi-Jie Liu
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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
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Article
| Open AccessThe architecture of transmembrane and cytoplasmic juxtamembrane regions of Toll-like receptors
Toll-like receptors (TLRs) play a key role in the innate immune system. Here, Kornilov et al. resolve the 3D structures of the membrane-associated parts of four TLRs to reveal properties of the juxta-membrane domain.
- F. D. Kornilov
- , A. V. Shabalkina
- & K. S. Mineev
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Article
| Open AccessMechanism underlying delayed rectifying in human voltage-mediated activation Eag2 channel
Human Eag2 is a voltage-gated potassium channel with unique delayed rectifying gating kinetics. Here, authors show how voltage opens the channel and illuminate a mechanism of delayed rectifier gating.
- Mingfeng Zhang
- , Yuanyue Shan
- & Duanqing Pei
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Article
| Open AccessStructural basis of vitamin C recognition and transport by mammalian SVCT1 transporter
Sodium-dependent vitamin C transporters are responsible for vitamin C uptake and tissue distribution in mammals. Here, authors present cryo-EM structures of mouse SVCT1 in both the apo and substrate-bound states, revealing the structural basis of substrate recognition and transport.
- Mingxing Wang
- , Jin He
- & Ji She
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Article
| Open AccessCryo-EM structures of human Cx36/GJD2 neuronal gap junction channel
Connexin 36 (Cx36) gap junction channel is responsible for signal transmission in electrical synapses. Here, the authors determine cryo-EM structures of Cx36, providing insights into a potential role of lipids in the channel gating.
- Seu-Na Lee
- , Hwa-Jin Cho
- & Hyung Ho Lee
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Article
| Open AccessIntermediate-state-trapped mutants pinpoint G protein-coupled receptor conformational allostery
Understanding of GPCR activation is limited as the structural information fails to present the full spectrum of energy landscape. Here, authors establish a series of conformation-biased mutants that represent five conformational states lying along adenosine A2A receptor (A2AR) activation.
- Xudong Wang
- , Chris Neale
- & Libin Ye
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Article
| Open AccessTwo-step structural changes in M3 muscarinic receptor activation rely on the coupled Gq protein cycle
During Gq protein activation, the separated Gαq-GTP forms a stable complex with the ligand-activated hM3R and PLCβ. Here the authors demonstrate that a single M3 receptor FRET probe can display the real-time conformational dynamics of innate receptor by the downstream Gq protein cycle.
- Yong-Seok Kim
- , Jun-Hee Yeon
- & Byung-Chang Suh
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Article
| Open AccessPhotocrosslinking-induced CRAC channel-like Orai1 activation independent of STIM1
The Ca2+ ion channel Orai1 is crucial in immune cells. Here, the authors applied genetic code expansion to transfer light-sensitivity to the Orai1 channel and achieved precise control over its function.
- Lena Maltan
- , Sarah Weiß
- & Isabella Derler
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Article
| Open AccessStructural basis of peptide recognition and activation of endothelin receptors
Endothelin receptors (ETAR and ETBR) are critical for vasoregulation and are targets for cardiovascular diseases treatment. Here, the authors offer a structural basis for peptide recognition selectivity and activation of both endothelin receptors.
- Yujie Ji
- , Jia Duan
- & Yi Jiang
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Article
| Open AccessOptical control of PIEZO1 channels
PIEZO proteins are large, mechanically-activated trimeric ion channels. Here the authors report a light-gated mouse PIEZO1 channel, mOP1, whereby an azobenzene-based photoswitch covalently localised at the extracellular apex of a transmembrane helix, rapidly triggers channel gating on light irradiation.
- Francisco Andrés Peralta
- , Mélaine Balcon
- & Thomas Grutter
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Article
| Open AccessCryo-EM structure of human heptameric pannexin 2 channel
Pannexin 2 plays critical roles in many physiological processes but its mechanism remain unclear. Here, authors report the cryo-EM structure of human Panx2 in the open state and identify critical residues for its gating.
- Hang Zhang
- , Shiyu Wang
- & Huawei Zhang
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Article
| Open AccessNoncanonical electromechanical coupling paths in cardiac hERG potassium channel
Potassium channels allow vital organ such as brain, heart, and muscles to function. Here, authors reveal the existence of a noncanonical kinematic chain of residues involving the S4/S1 and S1/S5 subunit interfaces that controls the gating of the hERG cardiac channel.
- Carlos A. Z. Bassetto Jr
- , Flavio Costa
- & Alberto Giacomello
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Article
| Open AccessStructural basis of lysophosphatidylserine receptor GPR174 ligand recognition and activation
GPR174 is a lysophosphatidylserine (LysoPS) activated GPCR. Here, the authors report the cryo-EM structure of LysoPS-bound human GPR174 in complex with Gs protein. The study reveals how GPR174 recognizes the lipid ligand and engages Gs in a distinct binding mode.
- Jiale Liang
- , Asuka Inoue
- & Yuanzheng He