Abstract:
:Type-A γ-aminobutyric (GABAA) receptors are ligand-gated chloride channels with a very rich pharmacology. Some of their modulators, including benzodiazepines and general anaesthetics, are among the most successful drugs in clinical use and are common substances of abuse. Without reliable structural data, the mechanistic basis for the pharmacological modulation of GABAA receptors remains largely unknown. Here we report several high-resolution cryo-electron microscopy structures in which the full-length human α1β3γ2L GABAA receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA (γ-aminobutyric acid), and the classical benzodiazepines alprazolam and diazepam. We describe the binding modes and mechanistic effects of these ligands, the closed and desensitized states of the GABAA receptor gating cycle, and the basis for allosteric coupling between the extracellular, agonist-binding region and the transmembrane, pore-forming region. This work provides a structural framework in which to integrate previous physiology and pharmacology research and a rational basis for the development of GABAA receptor modulators.
journal_name
Naturejournal_title
Natureauthors
Masiulis S,Desai R,Uchański T,Serna Martin I,Laverty D,Karia D,Malinauskas T,Zivanov J,Pardon E,Kotecha A,Steyaert J,Miller KW,Aricescu ARdoi
10.1038/s41586-018-0832-5subject
Has Abstractpub_date
2019-01-01 00:00:00pages
454-459issue
7740eissn
0028-0836issn
1476-4687pii
10.1038/s41586-018-0832-5journal_volume
565pub_type
杂志文章相关文献
NATURE文献大全abstract::The signal recognition particle (SRP) consists of one RNA and six protein subunits. The N-terminal domain of the 54K subunit contains a putative GTP-binding site, whereas the C-terminal domain binds signal sequences and SRP RNA. Binding of SRP to the signal sequence as it emerges from the ribosome creates a cytosolic ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/366351a0
更新日期:1993-11-25 00:00:00
abstract::A soluble enzyme system has been discovered which specifically recognizes and replicates plasmids containing the Escherichia coli chromosomal origin, oriC. Electron microscopy has shown that plasmid replication begins at or near oriC from which it progresses bidirectionally to completion. Control of initiation of a cy...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/296623a0
更新日期:1982-04-15 00:00:00
abstract::The crystal structure of a solid controls the interactions between the electronically active units and thus its electronic properties. In the high-temperature superconducting copper oxides, only one spatial arrangement of the electronically active Cu(2+) units-a two-dimensional square lattice-is available to study the...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature09120
更新日期:2010-07-08 00:00:00
abstract::Clouds on Titan result from the condensation of methane and ethane and, as on other planets, are primarily structured by circulation of the atmosphere. At present, cloud activity mainly occurs in the southern (summer) hemisphere, arising near the pole and at mid-latitudes from cumulus updrafts triggered by surface hea...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature08014
更新日期:2009-06-04 00:00:00
abstract::The 37-amino-acid calcitonin gene-related peptide (CGRP) occurs as a result of alternative processing of mRNA from the calcitonin gene. The potency of CGRP as a vasodilator and the occurrence of the peptide in nerves associated with blood vessels suggest an important role for CGRP in the regulation of blood flow. The ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/335073a0
更新日期:1988-09-01 00:00:00
abstract::The lack of a reliable theory of glass physics has led to the pursuit of correlations between various glass or viscous liquid parameters, one of which is the slope m of the plot of log(viscosity) against Tg/T, extrapolated at the glass-transition temperature, Tg, also termed 'fragility'. Novikov and Sokolov conclude t...
journal_title:Nature
pub_type: 评论,杂志文章
doi:10.1038/nature04967
更新日期:2006-08-03 00:00:00
abstract::A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself after injury. We recently demonstrated that the early postnatal mammalian heart is capable of regeneration following injury through proliferation of preexisting cardiomyocytes1,2 and that Meis1, a three am...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-020-2228-6
更新日期:2020-06-01 00:00:00
abstract::Cell-free DNA in the blood provides a non-invasive diagnostic avenue for patients with cancer1. However, characteristics of the origins and molecular features of cell-free DNA are poorly understood. Here we developed an approach to evaluate fragmentation patterns of cell-free DNA across the genome, and found that prof...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-019-1272-6
更新日期:2019-06-01 00:00:00
abstract::To identify cis-acting DNA elements involved in the activation of the alpha-fetoprotein gene during differentiation, modified copies of the gene were introduced into murine F9 embryonal carcinoma cells. The differentiation of the transformants to either parietal or visceral endoderm was accompanied by induction of the...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/310562a0
更新日期:1984-08-16 00:00:00
abstract::The maturation of RAS GTPases and approximately 200 other cellular CAAX proteins involves three enzymatic steps: addition of a farnesyl or geranylgeranyl prenyl lipid to the cysteine (C) in the C-terminal CAAX motif, proteolytic cleavage of the AAX residues and methylation of the exposed prenylcysteine residue at its ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature25439
更新日期:2018-01-25 00:00:00
abstract::L-glutamate, the neurotransmitter of the majority of excitatory synapses in the brain, acts on three classes of ionotropic receptors: NMDA (N-methyl-D-aspartate), AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) and kainate receptors. Little is known about the physiological role of kainate receptors be...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/33408
更新日期:1998-04-09 00:00:00
abstract::Design-specific control over excited-state dynamics is necessary for any application seeking to convert light into chemical potential. Such control is especially desirable in iron(II)-based chromophores, which are an Earth-abundant option for a wide range of photo-induced electron-transfer applications including solar...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-020-2353-2
更新日期:2020-06-01 00:00:00
abstract::Change history: In this Letter, the bottom blot in Fig. 2g (for 'IB: Myc') was missing. This has been corrected online. ...
journal_title:Nature
pub_type: 已发布勘误
doi:10.1038/s41586-019-1360-7
更新日期:2019-07-01 00:00:00
abstract::Deuterostomes are a remarkably diverse super-phylum, including not only the chordates (to which we belong) but groups as disparate as the echinoderms and the hemichordates. The phylogeny of deuterostomes is now achieving some degree of stability, especially on account of new molecular data, but this leaves as conjectu...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature02648
更新日期:2004-07-22 00:00:00
abstract::The transcriptional underpinnings of brain development remain poorly understood, particularly in humans and closely related non-human primates. We describe a high-resolution transcriptional atlas of rhesus monkey (Macaca mulatta) brain development that combines dense temporal sampling of prenatal and postnatal periods...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature18637
更新日期:2016-07-21 00:00:00
abstract::Optical structures with periodic variations of the dielectric constant in one or more directions (photonic crystals) have been employed extensively for studying optical diffraction phenomena. Practical interest in such structures arises from the possibilities they offer for tailoring photon modes, and thereby the char...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/35038026
更新日期:2000-10-19 00:00:00
abstract::Regulation of transcription initiation by proteins binding at DNA sequences some distance from the promoter region itself seems to be a general phenomenon in both eukaryotes and prokaryotes. Proteins bound to an enhancer site in eukaryotes can turn on a distant gene, whereas efficient repression of some prokaryotic ge...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/325823a0
更新日期:1987-02-26 00:00:00
abstract::Although there are substantial differences between the magnetospheres of Jupiter and Saturn, it has been suggested that cryovolcanic activity at Enceladus could lead to electrodynamic coupling between Enceladus and Saturn like that which links Jupiter with Io, Europa and Ganymede. Powerful field-aligned electron beams...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature09928
更新日期:2011-04-21 00:00:00
abstract::Enveloped viruses have evolved complex glycoprotein machinery that drives the fusion of viral and cellular membranes, permitting entry of the viral genome into the cell. For the paramyxoviruses, the fusion (F) protein catalyses this membrane merger and entry step, and it has been postulated that the F protein undergoe...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature04322
更新日期:2006-01-05 00:00:00
abstract::Measurements of the cosmic microwave background (CMB) radiation can reveal with remarkable precision the conditions of the Universe when it was approximately 400,000 years old. The three most fundamental properties of the CMB are its frequency spectrum (which determines the temperature), and the fluctuations in both t...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature01271
更新日期:2002-12-19 00:00:00
abstract::Recent studies have demonstrated that monkeys and humans can use signals from the brain to guide computer cursors. Brain-computer interfaces (BCIs) may one day assist patients suffering from neurological injury or disease, but relatively low system performance remains a major obstacle. In fact, the speed and accuracy ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature04968
更新日期:2006-07-13 00:00:00
abstract::Activity in the motor cortex predicts movements, seconds before they are initiated. This preparatory activity has been observed across cortical layers, including in descending pyramidal tract neurons in layer 5. A key question is how preparatory activity is maintained without causing movement, and is ultimately conver...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-018-0642-9
更新日期:2018-11-01 00:00:00
abstract::Two cytosolic fractions (A and B) from Xenopus oocytes are sufficient to support protein import into the nuclei of digitonin-permeabilized cells. Fraction A recognizes the nuclear localization sequence (NLS) and binds the import substrate to the nuclear envelope, whereas fraction B mediates the subsequent passage of t...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/365661a0
更新日期:1993-10-14 00:00:00
abstract::Rac signalling to actin -- a pathway that is thought to be mediated by the protein Scar/WAVE (WASP (Wiskott-Aldrich syndrome protein)-family verprolin homologous protein -- has a principal role in cell motility. In an analogous pathway, direct interaction of Cdc42 with the related protein N-WASP stimulates actin polym...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature00859
更新日期:2002-08-15 00:00:00
abstract::Although cell adhesion to substrate must ultimately depend on 'sticking' by physical forces at the outer surface, we suggest that control is exercised through the 'grip' of the cytoskeleton. Our experiments indicate that grip can be relaxed by agents which release surface glycoproteins from some form of side-to-side o...
journal_title:Nature
pub_type: 杂志文章,评审
doi:10.1038/267124a0
更新日期:1977-05-12 00:00:00
abstract::Despite active transport into Earth's mantle, water has been present on our planet's surface for most of geological time. Yet water disappeared from the Martian surface soon after its formation. Although some of the water on Mars was lost to space via photolysis following the collapse of the planet's magnetic field, t...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature25031
更新日期:2017-12-20 00:00:00
abstract::Blood production is ensured by rare, self-renewing haematopoietic stem cells (HSCs). How HSCs accommodate the diverse cellular stresses associated with their life-long activity remains elusive. Here we identify autophagy as an essential mechanism protecting HSCs from metabolic stress. We show that mouse HSCs, in contr...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature11895
更新日期:2013-02-21 00:00:00
abstract::Multiple sclerosis is thought to be an autoimmune disease of the central nervous system mediated by T cells specific for a myelin antigen. Myelin basic protein has been studied as a potential autoantigen in the disease because of its role as an encephalitogen in experimental autoimmune encephalomyelitis and post-viral...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/346183a0
更新日期:1990-07-12 00:00:00
abstract::Diminishing fossil fuel reserves and growing concerns about global warming indicate that sustainable sources of energy are needed in the near future. For fuels to be useful in the transportation sector, they must have specific physical properties that allow for efficient distribution, storage and combustion; these pro...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature05923
更新日期:2007-06-21 00:00:00
abstract::Synaptic transmission of most vertebrate synapses is thought to be terminated by rapid transport of the neurotransmitter into presynaptic nerve terminals or neuroglia. L-Glutamate is the major excitatory transmitter in brain and its transport represents the mechanism by which it is removed from the synaptic cleft and ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/360464a0
更新日期:1992-12-03 00:00:00