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Structural and molecular basis of choline uptake into the brain by FLVCR2
FLVCR2 is expressed in the blood–brain barrier of mouse and human, and is the major mediator of choline uptake into the brain.
- Rosemary J. Cater
- , Dibyanti Mukherjee
- & Filippo Mancia
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Article |
Structural insights into vesicular monoamine storage and drug interactions
Monoamines and neurotoxicants share a binding pocket in VMAT1 featuring polar sites for specificity and a wrist-and-fist shape for versatility, and monoamine enrichment in storage vesicles arises from dominant import via favoured lumenal-open transition of VMAT1 and protonation-precluded binding during its cytoplasmic-open transition.
- Jin Ye
- , Huaping Chen
- & Weikai Li
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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 stimulated by a G-protein-coupled receptor.
- Makaía M. Papasergi-Scott
- , Guillermo Pérez-Hernández
- & Georgios Skiniotis
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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 AccessStructures of a sperm-specific solute carrier gated by voltage and cAMP
This study proposes a molecular mechanism of voltage activation in SLC9C1, a transporter essential for male fertility.
- Valeria Kalienkova
- , Martin F. Peter
- & Cristina Paulino
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Article |
Structure of an endogenous mycobacterial MCE lipid transporter
Proteins of the Mycobacterium smegmatis Mce1 system assemble to form an elongated ABC transporter complex that is long enough to span the impermeable mycobacterial cell envelope.
- James Chen
- , Alice Fruhauf
- & Damian C. Ekiert
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Article |
Structural basis for the binding of DNP and purine nucleotides onto UCP1
Using cryo-electron microscopy, the structures of human UCP1 in the nucleotide-free state, the DNP activator-bound state, and the inhibitory ATP-bound state are resolved, providing details of how purine nucleotides inhibit UCP1.
- Yunlu Kang
- & Lei Chen
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Article
| Open AccessÅngström-resolution fluorescence microscopy
The authors introduce a single-molecule DNA-barcoding method, resolution enhancement by sequential imaging, that improves the resolution of fluorescence microscopy down to the Ångström scale using off-the-shelf fluorescence microscopy hardware and reagents.
- Susanne C. M. Reinhardt
- , Luciano A. Masullo
- & Ralf Jungmann
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Article |
Structural basis of BAM-mediated outer membrane β-barrel protein assembly
The structural basis of the late-stage intermediate assembly of outer membrane β-barrel proteins mediated by the bacterial β-barrel assembly machinery is determined.
- Chongrong Shen
- , Shenghai Chang
- & Haohao Dong
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Article |
Noncoding translation mitigation
Combining genome-wide CRISPR screens with massively parallel analyses of human and random DNA sequences reveal a unified mechanism for the surveillance and evolution of translation products from annotated noncoding DNA.
- Jordan S. Kesner
- , Ziheng Chen
- & Xuebing Wu
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Article
| Open AccessCFTR function, pathology and pharmacology at single-molecule resolution
A structure–function analysis of cystic fibrosis transmembrane conductance regulator shows its two nucleotide-binding domains dimerize before channel opening, and reveals a mechanism through which conformational changes in the channel regulate chloride conductance.
- Jesper Levring
- , Daniel S. Terry
- & Jue Chen
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Article |
Architecture of chloroplast TOC–TIC translocon supercomplex
A cryo-electron microscopy analysis of the Chlamydomonas reinhardtii TOC–TIC supercomplex reveals that Tic214 traverses the chloroplast inner membrane, the intermembrane space and the outer membrane, connecting the TOC complex with the TIC proteins.
- Hao Liu
- , Anjie Li
- & Zhenfeng Liu
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Article |
Recognition of cyclic dinucleotides and folates by human SLC19A1
Two cyclic dinucleotide molecules bind within the cavity of human SLC19A1 as a compact dual-molecule unit, whereas folate and antifolate bind to SLC19A1 as a monomer and occupy a distinct pocket of the cavity.
- Qixiang Zhang
- , Xuyuan Zhang
- & Pu Gao
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Article
| Open AccessStructural insights into auxin recognition and efflux by Arabidopsis PIN1
Structures of the Arabidopsis thaliana auxin exporter PIN1 in the apo state, bound to the natural auxin or bound to an inhibitor provide insights into the polar auxin transport mechanisms mediated by PIN family transporters.
- Zhisen Yang
- , Jing Xia
- & Linfeng Sun
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Structural basis of GABA reuptake inhibition
Structural determination of GAT1 using cryo-electron microscopy provides insights into the biology and pharmacology of this GABA transporter.
- Zenia Motiwala
- , Nanda Gowtham Aduri
- & Cornelius Gati
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Article |
Tethered peptide activation mechanism of the adhesion GPCRs ADGRG2 and ADGRG4
Cryo-electron microscopy structures of three adhesion G protein-coupled receptors (aGPCRs) complexes provide insight into the tethered activation mechanism of aGPCRs and show the potential for rational design of agonists.
- Peng Xiao
- , Shengchao Guo
- & Xiao Yu
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Article |
Structural basis of lipopolysaccharide maturation by the O-antigen ligase
Cryo-electron microscopy structures of the bacterial O-antigen ligase WaaL, combined with genetics, biochemistry and molecular dynamics simulations, provide insight into the mechanism by which WaaL catalyses the biosynthesis of lipopolysaccharide.
- Khuram U. Ashraf
- , Rie Nygaard
- & Filippo Mancia
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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 is stabilized 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 |
Structural basis of omega-3 fatty acid transport across the blood–brain barrier
Cryo-electron microscopy and molecular dynamics simulations reveal how MFSD2A transports essential omega-3 fatty acids across the blood–brain and blood–retina barriers as lysolipids.
- Rosemary J. Cater
- , Geok Lin Chua
- & Filippo Mancia
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Article
| Open AccessStructure and dynamics of a mycobacterial type VII secretion system
A cryo-electron microscopy structure of the inner membrane complex of the ESX-5 type VII secretion system of Mycobacterium tuberculosis reveals an important role of interactions with MycP5 protease for complex integrity.
- Catalin M. Bunduc
- , Dirk Fahrenkamp
- & Thomas C. Marlovits
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Article |
Capping pores of alphavirus nsP1 gate membranous viral replication factories
Cryo-electron microscopy structures of non-structural protein 1 (nsP1) of chikungunya virus reveal the mechanisms that underpin the association of viral replication machinery with virus-induced membranous organelles within host cells.
- Rhian Jones
- , Gabriel Bragagnolo
- & Juan Reguera
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Article |
Computational design of transmembrane pores
An approach for the design of protein pores is demonstrated by the computational design and subsequent experimental expression of both an ion-selective and a large transmembrane pore.
- Chunfu Xu
- , Peilong Lu
- & David Baker
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Article |
Structure of hepcidin-bound ferroportin reveals iron homeostatic mechanisms
Structures of the iron transporter ferroportin and the peptide hormone hepcidin suggest how iron homeostasis is tightly regulated.
- Christian B. Billesbølle
- , Caleigh M. Azumaya
- & Aashish Manglik
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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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Structure of a nascent membrane protein as it folds on the BAM complex
Cryo-electron microscopy structures of a folding intermediate on the BAM complex of Escherichia coli reveal how interactions between the BamA catalyst and substrate permit stable association during folding, followed by rapid turnover.
- David Tomasek
- , Shaun Rawson
- & Daniel Kahne
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Article |
LEM2 phase separation promotes ESCRT-mediated nuclear envelope reformation
Following cell division, phase separation of the transmembrane adaptor LEM2 ensures that the ESCRT machinery remodels microtubules and seals the nuclear envelope.
- Alexander von Appen
- , Dollie LaJoie
- & Adam Frost
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Article |
A mycobacterial ABC transporter mediates the uptake of hydrophilic compounds
Analysis of cryo-electron microscopy structures of the Mycobacterium tuberculosis ABC transporter Rv1819c suggests that it is a multi-solute transporter for hydrophilic molecules.
- S. Rempel
- , C. Gati
- & D. J. Slotboom
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Article |
Structure and mechanism of the ER-based glucosyltransferase ALG6
Analyses reveal a previously undescribed transmembrane protein fold in the endoplasmic reticulum-based glucosyltransferase ALG6 and provide a structural basis for understanding the glucose transfer mechanism.
- Joël S. Bloch
- , Giorgio Pesciullesi
- & Kaspar P. Locher
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Letter |
Structural basis of unidirectional export of lipopolysaccharide to the cell surface
Crystal structures of a five-protein complex comprising the inner-membrane components of the bacterial lipopolysaccharide transporter provide insight into the mechanism of extraction of lipopolysaccharide from the inner membrane and its transport to the outer membrane.
- Tristan W. Owens
- , Rebecca J. Taylor
- & Daniel Kahne
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Letter |
Structure of the human LAT1–4F2hc heteromeric amino acid transporter complex
The cryo-EM structure of the LAT1–4F2hc complex, a heteromeric amino acid transporter, is characterized, providing insights into its function and the mechanisms through which mutations of this complex could cause disease.
- Renhong Yan
- , Xin Zhao
- & Qiang Zhou
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Article |
Structural insights into the activation of metabotropic glutamate receptors
The activation mechanism of metabotropic glutamate receptor subtype 5, a member of the family C G-protein-coupled receptors, is characterized by a combination of cryo-electron microscopy, crystallography and signalling studies.
- Antoine Koehl
- , Hongli Hu
- & Brian K. Kobilka
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Letter |
Cryo-EM structures of a human ABCG2 mutant trapped in ATP-bound and substrate-bound states
Cryo-electron microscopy structures of the ABCG2 protein in ATP- and substrate-bound states reveal the location of substrate binding, conformational changes required for substrate translocation and how inhibitors might be distinguished from substrates.
- Ioannis Manolaridis
- , Scott M. Jackson
- & Kaspar P. Locher
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Article |
Cryo-EM structures of fungal and metazoan mitochondrial calcium uniporters
Structures of the mitochondrial calcium uniporter from fungal and metazoan organisms reveal a tetrameric architecture and shed light on the function of the channel.
- Rozbeh Baradaran
- , Chongyuan Wang
- & Stephen Barstow Long
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Letter |
Structure of the alternative complex III in a supercomplex with cytochrome oxidase
The structure of alternative complex III, a key enzyme in the bacterial electron transport chain, is reported both alone and as a supercomplex with an aa3-type cytochrome c oxidase.
- Chang Sun
- , Samir Benlekbir
- & Robert B. Gennis
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Article |
Crystal structures of the gastric proton pump
Crystal structures of the gastric proton pump in complex with two inhibitory drugs reveal the mechanism that generates the steep acidic gradient across the membranes of parietal cells.
- Kazuhiro Abe
- , Katsumasa Irie
- & Yoshinori Fujiyoshi
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Letter |
Crystal structure of the potassium-importing KdpFABC membrane complex
The crystal structure of the bacterial potassium import complex KdpFABC shows how ATP hydrolysis is coupled to potassium transport to maintain cellular homeostasis under low potassium conditions.
- Ching-Shin Huang
- , Bjørn Panyella Pedersen
- & David L. Stokes
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Article |
Structure of the human multidrug transporter ABCG2
The structure of human ABCG2 bound to an inhibitory antibody using cryo-electron microscopy, representing the first high-resolution structural data of a human multidrug transporter.
- Nicholas M. I. Taylor
- , Ioannis Manolaridis
- & Kaspar P. Locher
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Article |
Structure and allosteric inhibition of excitatory amino acid transporter 1
High-resolution structures of the thermostabilized human excitatory amino acid transporter EAAT1, alone or in association with its substrate or small molecule inhibitors, reveal architectural features of human SLC1 transporters and an allosteric mechanism of inhibition.
- Juan C. Canul-Tec
- , Reda Assal
- & Nicolas Reyes
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Review Article |
Organization and functions of mGlu and GABAB receptor complexes
This Review discusses current knowledge of the structure, function and interactions of the metabotropic glutamate and GABAB receptors and the potential to target receptor subunits for future therapeutic intervention in neurological and mental health disorders.
- Jean-Philippe Pin
- & Bernhard Bettler
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Letter |
High-resolution crystal structure of the human CB1 cannabinoid receptor
The authors report a 2.6 Å resolution crystal structure of the human CB1 cannabinoid receptor trapped in the inactive conformation and bound to the antagonist taranabant.
- Zhenhua Shao
- , Jie Yin
- & Daniel M. Rosenbaum
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Letter |
Atomic model for the membrane-embedded VO motor of a eukaryotic V-ATPase
The structure of the VO subcomplex of yeast V-ATPase, solved by electron cryomicroscopy, reveals a new subunit and suggests a mechanism for the translocation of protons across membranes.
- Mohammad T. Mazhab-Jafari
- , Alexis Rohou
- & John L. Rubinstein
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Article |
The architecture of respiratory supercomplexes
Respirasomes are supercomplexes of mitochondrial electron transport chain complexes that are responsible for cellular respiration and energy production; cryo-electron microscopy structures of mammalian (sheep) respirasomes are presented.
- James A. Letts
- , Karol Fiedorczuk
- & Leonid A. Sazanov
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Letter |
Accessory subunits are integral for assembly and function of human mitochondrial complex I
Gene-editing technology and large-scale proteomics are used to provide insights into the modular assembly of the human mitochondrial respiratory chain complex I, as well as identifying new assembly factors.
- David A. Stroud
- , Elliot E. Surgenor
- & Michael T. Ryan
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Letter |
Structural basis for amino acid export by DMT superfamily transporter YddG
The X-ray structure of the drug/metabolite transporter (DMT) protein YddG from Starkeya novella reveals a new membrane transport topology, with ten transmembrane segments in an outward-facing state and two pseudo-symmetric inverted structural repeats.
- Hirotoshi Tsuchiya
- , Shintaro Doki
- & Osamu Nureki
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Article |
X-ray structures and mechanism of the human serotonin transporter
X-ray crystal structures of the human serotonin transporter (SERT) bound to the antidepressants (S)-citalopram or paroxetine show that the antidepressants lock the protein in an outward-open conformation, and directly block serotonin from entering its binding site; the structures define the mechanism of antidepressant action in SERT and pave the way for future drug design.
- Jonathan A. Coleman
- , Evan M. Green
- & Eric Gouaux
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Letter |
Crystal structure of the human σ1 receptor
The X-ray crystal structures of the human σ1 receptor bound to two different ligands are reported, revealing the overall architecture, oligomerization state, and molecular basis for ligand recognition by this protein.
- Hayden R. Schmidt
- , Sanduo Zheng
- & Andrew C. Kruse
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Letter |
Crystal structure of human glycine receptor-α3 bound to antagonist strychnine
The X-ray crystal structure of the human glycine receptor in the presence of strychnine, an antagonist, reveals how antagonist binding leads to closure of the channel pore.
- Xin Huang
- , Hao Chen
- & Paul L. Shaffer
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Article |
Glycine receptor mechanism elucidated by electron cryo-microscopy
A high-resolution electron cryo-microscopy structure of the zebrafish α1 glycine receptor bound to agonists or antagonists reveals the conformational changes that take place when the channel transitions from closed to open state.
- Juan Du
- , Wei Lü
- & Eric Gouaux
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Article |
Crystal structures of a polypeptide processing and secretion transporter
Gram-positive bacteria use peptidase-containing ATP-binding cassette transporters (PCATs) to export quorum-sensing and antimicrobial polypeptides; here, the X-ray crystal structures of PCAT1 from Clostridium thermocellum in the absence and presence of ATP are reported.
- David Yin-wei Lin
- , Shuo Huang
- & Jue Chen