Allosteric potentiation of a ligand-gated ion channel is mediated by access to a deep membrane-facing cavity.

Abstract:

:Theories of general anesthesia have shifted in focus from bulk lipid effects to specific interactions with membrane proteins. Target receptors include several subtypes of pentameric ligand-gated ion channels; however, structures of physiologically relevant proteins in this family have yet to define anesthetic binding at high resolution. Recent cocrystal structures of the bacterial protein GLIC provide snapshots of state-dependent binding sites for the common surgical agent propofol (PFL), offering a detailed model system for anesthetic modulation. Here, we combine molecular dynamics and oocyte electrophysiology to reveal differential motion and modulation upon modification of a transmembrane binding site within each GLIC subunit. WT channels exhibited net inhibition by PFL, and a contraction of the cavity away from the pore-lining M2 helix in the absence of drug. Conversely, in GLIC variants exhibiting net PFL potentiation, the cavity was persistently expanded and proximal to M2. Mutations designed to favor this deepened site enabled sensitivity even to subclinical concentrations of PFL, and a uniquely prolonged mode of potentiation evident up to ∼30 min after washout. Dependence of these prolonged effects on exposure time implicated the membrane as a reservoir for a lipid-accessible binding site. However, at the highest measured concentrations, potentiation appeared to be masked by an acute inhibitory effect, consistent with the presence of a discrete, water-accessible site of inhibition. These results support a multisite model of transmembrane allosteric modulation, including a possible link between lipid- and receptor-based theories that could inform the development of new anesthetics.

authors

Heusser SA,Lycksell M,Wang X,McComas SE,Howard RJ,Lindahl E

doi

10.1073/pnas.1809650115

subject

Has Abstract

pub_date

2018-10-16 00:00:00

pages

10672-10677

issue

42

eissn

0027-8424

issn

1091-6490

pii

1809650115

journal_volume

115

pub_type

杂志文章
  • Efficient screening of retroviral cDNA expression libraries.

    abstract::Expression cloning of cDNAs was first described a decade ago and was based on transient expression of cDNA libraries in COS cells. In contrast to transient transfection of plasmids, retroviral gene transfer delivers genes stably into a wide range of target cells. We utilize a simple packaging system for production of ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.92.20.9146

    authors: Kitamura T,Onishi M,Kinoshita S,Shibuya A,Miyajima A,Nolan GP

    更新日期:1995-09-26 00:00:00

  • Novel template requirements of N4 virion RNA polymerase.

    abstract::A DNA-dependent RNA polymerase has been purified from disrupted virions of the Escherichia coli bacteriophage N4. The RNA polymerase is phage-coded and is required for class I N4 RNA synthesis, which is defined as RNA synthesized in vivo in the absence of post-infection protein synthesis. A polypeptide of molecular we...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.75.7.3220

    authors: Falco SC,Zivin R,Rothman-Denes LB

    更新日期:1978-07-01 00:00:00

  • Round-the-clock power supply and a sustainable economy via synergistic integration of solar thermal power and hydrogen processes.

    abstract::We introduce a paradigm-"hydricity"-that involves the coproduction of hydrogen and electricity from solar thermal energy and their judicious use to enable a sustainable economy. We identify and implement synergistic integrations while improving each of the two individual processes. When the proposed integrated process...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1513488112

    authors: Gençer E,Mallapragada DS,Maréchal F,Tawarmalani M,Agrawal R

    更新日期:2015-12-29 00:00:00

  • Assembly of the functional membrane attack complex of human complement: formation of disulfide-linked C9 dimers.

    abstract::The 158,000 Mr protein, previously designated C5c, present in fully assembled complement (C) membrane attack complexes (MC5b-9) has been identified as a disulfide-bonded dimer of C9. This conclusion was based on the observations that: (i) a portion of the 125I-radiolabeled precursor C9 incorporated into MC5b-9 complex...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.78.10.6426

    authors: Ware CF,Kolb WP

    更新日期:1981-10-01 00:00:00

  • Role for CD47-SIRPalpha signaling in xenograft rejection by macrophages.

    abstract::We have previously proven that human macrophages can phagocytose porcine cells even in the absence of Ab or complement opsonization, indicating that macrophages present a pivotal immunological obstacle to xenotransplantation. A recent report indicates that the signal regulatory protein (SIRP)alpha is a critical immune...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0609661104

    authors: Ide K,Wang H,Tahara H,Liu J,Wang X,Asahara T,Sykes M,Yang YG,Ohdan H

    更新日期:2007-03-20 00:00:00

  • Autologous and allogeneic typing of human leukemia cells: definition of surface antigens restricted to lymphocytic leukemia cells.

    abstract::Serum from a patient (CO) with acute lymphoblastic leukemia was reactive in immunoadherence assays with autologous leukemia cells but not with autologous blood lymphocytes or bone marrow cells during complete remission. Extensive absorption tests with an array of leukemia cells and normal cells were performed in order...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.80.8.2341

    authors: Naito K,Yamaguchi H,Horibe K,Shiku H,Takahashi T,Suzuki S,Yamada K

    更新日期:1983-04-01 00:00:00

  • An atomic resolution view of ICAM recognition in a complex between the binding domains of ICAM-3 and integrin alphaLbeta2.

    abstract::Within the Ig superfamily (IgSF), intercellular adhesion molecules (ICAMs) form a subfamily that binds the leukocyte integrin alphaLbeta2. We report a 1.65-A-resolution crystal structure of the ICAM-3 N-terminal domain (D1) in complex with the inserted domain, the ligand-binding domain of alphaLbeta2. This high-resolu...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0500200102

    authors: Song G,Yang Y,Liu JH,Casasnovas JM,Shimaoka M,Springer TA,Wang JH

    更新日期:2005-03-01 00:00:00

  • Adult hemoglobins are synthesized in erythroid colonies in vitro derived from murine circulating hemopoietic progenitor cells during embryonic development.

    abstract::Circulating peripheral blood cells and disaggregated yolk sac cells were obtained from normal mouse embryos as early as day 9 of gestation, prior to the formation of the fetal liver. These were cultured in vitro in plasma clots or methylcellulose, in the presence of either embryonic fluid or adult spleen cell-conditio...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.79.9.2952

    authors: Wong PM,Clarke BJ,Carr DH,Chui DH

    更新日期:1982-05-01 00:00:00

  • Cell fusion induced by scrapie and Creutzfeldt-Jakob virus-infected brain preparations.

    abstract::Cell fusion was induced by brain extracts containing the scrapie virus and the virus of Creutzfeldt-Jakob disease. The assay involved quantitation of colony-forming ability in a double selection system, strandardized against fusion induced by Sendai virus. Correlation between the logarithm of virus dilution and the hy...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.75.6.2969

    authors: Kidson C,Moreau MC,Asher DM,Brown PW,Coon HG,Gajdusek DC,Gibbs CJ Jr

    更新日期:1978-06-01 00:00:00

  • Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity.

    abstract::N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces neuropathological and clinical abnormalities in humans, monkeys, and mice that closely resemble idiopathic parkinsonism. N-Methyl-4-phenylpyridine (MPP+), a metabolite of MPTP formed by monoamine oxidase B, is accumulated into striatal and cerebral cortical ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.82.7.2173

    authors: Javitch JA,D'Amato RJ,Strittmatter SM,Snyder SH

    更新日期:1985-04-01 00:00:00

  • Obligatory separation of hormone binding and biological response curves in systems dependent upon secondary mediators of hormone action.

    abstract::A mathematical model is presented that describes the effects of hormone concentration on receptor saturation and biological response in systems dependent upon the generation of a secondary mediator such as cyclic AMP. The analysis makes the following assumptions: (i) the binding of hormone to its receptor is a reversi...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.78.3.1366

    authors: Strickland S,Loeb JN

    更新日期:1981-03-01 00:00:00

  • Linkage between retinal ganglion cell density and the nonuniform spatial integration across the visual field.

    abstract::The ability to integrate visual information over space is a fundamental component of human pattern vision. Regardless of whether it is for detecting luminance contrast or for recognizing objects in a cluttered scene, the position of the target in the visual field governs the size of a window within which visual inform...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1817076116

    authors: Kwon M,Liu R

    更新日期:2019-02-26 00:00:00

  • DNA unzipped under a constant force exhibits multiple metastable intermediates.

    abstract::Single molecule studies, at constant force, of the separation of double-stranded DNA into two separated single strands may provide information relevant to the dynamics of DNA replication. At constant applied force, theory predicts that the unzipped length as a function of time is characterized by jumps during which th...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.262789199

    authors: Danilowicz C,Coljee VW,Bouzigues C,Lubensky DK,Nelson DR,Prentiss M

    更新日期:2003-02-18 00:00:00

  • Hollow core of Alzheimer's Abeta42 amyloid observed by cryoEM is relevant at physiological pH.

    abstract::Recent cryoEM density maps of Abeta(42) fibrils obtained at low pH revealed two protofilaments winding around a hollow core raising the question if such tubular structures also exist at physiological pH. Based on the cryoEM measurements and on NMR data, we probe amyloid fibril organizations corresponding to the observ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1004704107

    authors: Miller Y,Ma B,Tsai CJ,Nussinov R

    更新日期:2010-08-10 00:00:00

  • Probable precursors of [Leu]enkephalin and [Met]enkephalin in adrenal medulla: peptides of 3-5 kilodaltons.

    abstract::Adrenal chromaffin granules contain at least 10 peptides, ranging in size from 3 to 5 kilodaltons, that yield, upon digestion with trypsin, peptides that show specific binding to opiate receptors. All are distinctly different from beta-endorphin. Two of these peptides have been purified to homogeneity and subjected to...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.77.3.1681

    authors: Kimura S,Lewis RV,Stern AS,Rossier J,Stein S,Udenfriend S

    更新日期:1980-03-01 00:00:00

  • RNA polymerase subunit RPB5 plays a role in transcriptional activation.

    abstract::A mutation in RPB5 (rpb5-9), an essential RNA polymerase subunit assembled into RNA polymerases I, II, and III, revealed a role for this subunit in transcriptional activation. Activation by GAL4-VP16 was impaired upon in vitro transcription with mutant whole-cell extracts. In vivo experiments using inducible reporter ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.95.26.15281

    authors: Miyao T,Woychik NA

    更新日期:1998-12-22 00:00:00

  • Global impairment and therapeutic restoration of visual plasticity mechanisms after a localized cortical stroke.

    abstract::We tested the influence of a photothrombotic lesion in somatosensory cortex on plasticity in the mouse visual system and the efficacy of anti-inflammatory treatment to rescue compromised learning. To challenge plasticity mechanisms, we induced monocular deprivation (MD) in 3-mo-old mice. In control animals, MD induced...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1016458108

    authors: Greifzu F,Schmidt S,Schmidt KF,Kreikemeier K,Witte OW,Löwel S

    更新日期:2011-09-13 00:00:00

  • Lipid-protein interaction in the phosphatidylcholine exchange protein.

    abstract::Incorporation of 2-acyl spin-labeled lecithin into the phosphatidylcholine protein from bovine liver results in an immobilization of the spin-label at the methyl and the carboxyl terminal end of the acyl chain. The nitroxide group on the protein-bound lecithin molecule is not accessible to ascorbate. This suggests tha...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.74.5.1807

    authors: Devaux PF,Moonen P,Bienvenue A,Wirtz KW

    更新日期:1977-05-01 00:00:00

  • Molecular clock is involved in predictive circadian adjustment of renal function.

    abstract::Renal excretion of water and major electrolytes exhibits a significant circadian rhythm. This functional periodicity is believed to result, at least in part, from circadian changes in secretion/reabsorption capacities of the distal nephron and collecting ducts. Here, we studied the molecular mechanisms underlying circ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0904890106

    authors: Zuber AM,Centeno G,Pradervand S,Nikolaeva S,Maquelin L,Cardinaux L,Bonny O,Firsov D

    更新日期:2009-09-22 00:00:00

  • Structure of a two-domain chitotriosidase from Serratia marcescens at 1.9-A resolution.

    abstract::In this paper, we describe the structure of chitinase B from Serratia marcescens, which consists of a catalytic domain with a TIM-barrel fold and a 49-residue C-terminal chitin-binding domain. This chitinase is the first structure of a bacterial exochitinase, and it represents one of only a few examples of a glycosyl ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.97.11.5842

    authors: van Aalten DM,Synstad B,Brurberg MB,Hough E,Riise BW,Eijsink VG,Wierenga RK

    更新日期:2000-05-23 00:00:00

  • B-cell activation by crosslinking of surface IgM or ligation of CD40 involves alternative signal pathways and results in different B-cell phenotypes.

    abstract::Treatment of small resting B cells with soluble F(ab')2 fragments of anti-IgM, an analogue of T-independent type 2 antigens, induced activation characterized by proliferation and the expression of surface CD5. In contrast, B cells induced to proliferate in response to thymus-dependent inductive signals provided by eit...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.92.8.3348

    authors: Wortis HH,Teutsch M,Higer M,Zheng J,Parker DC

    更新日期:1995-04-11 00:00:00

  • Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis.

    abstract::RPE65 is a protein of unknown function expressed specifically by the retinal pigment epithelium. We examined all 14 exons of this gene in 147 unrelated patients with autosomal recessive retinitis pigmentosa (RP), in 15 patients with isolate RP, and in 45 patients with Leber congenital amaurosis (LCA). Sequence anomali...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.95.6.3088

    authors: Morimura H,Fishman GA,Grover SA,Fulton AB,Berson EL,Dryja TP

    更新日期:1998-03-17 00:00:00

  • Heterogeneity of long-history migration explains cultural differences in reports of emotional expressivity and the functions of smiles.

    abstract::A small number of facial expressions may be universal in that they are produced by the same basic affective states and recognized as such throughout the world. However, other aspects of emotionally expressive behavior vary widely across culture. Just why do they vary? We propose that some cultural differences in expre...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1413661112

    authors: Rychlowska M,Miyamoto Y,Matsumoto D,Hess U,Gilboa-Schechtman E,Kamble S,Muluk H,Masuda T,Niedenthal PM

    更新日期:2015-05-12 00:00:00

  • Evidence from central Mexico supporting the Younger Dryas extraterrestrial impact hypothesis.

    abstract::We report the discovery in Lake Cuitzeo in central Mexico of a black, carbon-rich, lacustrine layer, containing nanodiamonds, microspherules, and other unusual materials that date to the early Younger Dryas and are interpreted to result from an extraterrestrial impact. These proxies were found in a 27-m-long core as p...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 历史文章,杂志文章

    doi:10.1073/pnas.1110614109

    authors: Israde-Alcántara I,Bischoff JL,Domínguez-Vázquez G,Li HC,DeCarli PS,Bunch TE,Wittke JH,Weaver JC,Firestone RB,West A,Kennett JP,Mercer C,Xie S,Richman EK,Kinzie CR,Wolbach WS

    更新日期:2012-03-27 00:00:00

  • Monovalent antibodies directed to transformation-sensitive membrane components inhibit the process of viral transformation.

    abstract::Monovalent antibodies (Fab) directed to two classes of transformation-sensitive cell surface components, ganglioside and galactoprotein a (Gap a), inhibit the process of oncogenic viral transformation of cells. Mouse 3T3 cells infected with murine sarcoma virus were not transformed in terms of morphology change and en...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.75.12.6049

    authors: Lingwood CA,Ng A,Hakomori S

    更新日期:1978-12-01 00:00:00

  • Long-range compaction and flexibility of interphase chromatin in budding yeast analyzed by high-resolution imaging techniques.

    abstract::Little is known about how chromatin folds in its native state. Using optimized in situ hybridization and live imaging techniques have determined compaction ratios and fiber flexibility for interphase chromatin in budding yeast. Unlike previous studies, ours examines nonrepetitive chromatin at intervals short enough to...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0402766101

    authors: Bystricky K,Heun P,Gehlen L,Langowski J,Gasser SM

    更新日期:2004-11-23 00:00:00

  • The K+ channel KIR2.1 functions in tandem with proton influx to mediate sour taste transduction.

    abstract::Sour taste is detected by a subset of taste cells on the tongue and palate epithelium that respond to acids with trains of action potentials. Entry of protons through a Zn(2+)-sensitive proton conductance that is specific to sour taste cells has been shown to be the initial event in sour taste transduction. Whether th...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1514282112

    authors: Ye W,Chang RB,Bushman JD,Tu YH,Mulhall EM,Wilson CE,Cooper AJ,Chick WS,Hill-Eubanks DC,Nelson MT,Kinnamon SC,Liman ER

    更新日期:2016-01-12 00:00:00

  • Physical and genetic-interaction density reveals functional organization and informs significance cutoffs in genome-wide screens.

    abstract::Genome-wide experiments often measure quantitative differences between treated and untreated cells to identify affected strains. For these studies, statistical models are typically used to determine significance cutoffs. We developed a method termed "CLIK" (Cutoff Linked to Interaction Knowledge) that overlays biologi...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1219582110

    authors: Dittmar JC,Pierce S,Rothstein R,Reid RJ

    更新日期:2013-04-30 00:00:00

  • Cocaine reward is reduced by decreased expression of receptor-type protein tyrosine phosphatase D (PTPRD) and by a novel PTPRD antagonist.

    abstract::Receptor-type protein tyrosine phosphatase D (PTPRD) is a neuronal cell-adhesion molecule/synaptic specifier that has been implicated in addiction vulnerability and stimulant reward by human genomewide association and mouse cocaine-conditioned place-preference data. However, there have been no reports of effects of re...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1720446115

    authors: Uhl GR,Martinez MJ,Paik P,Sulima A,Bi GH,Iyer MR,Gardner E,Rice KC,Xi ZX

    更新日期:2018-11-06 00:00:00

  • Desoxyepothilone B is curative against human tumor xenografts that are refractory to paclitaxel.

    abstract::The epothilones are naturally occurring, cytotoxic macrolides that function through a paclitaxel (Taxol)-like mechanism. Although structurally dissimilar, both classes of molecules lead to the arrest of cell division and eventual cell death by stabilizing cellular microtubule assemblies. The epothilones differ in thei...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.95.26.15798

    authors: Chou TC,Zhang XG,Harris CR,Kuduk SD,Balog A,Savin KA,Bertino JR,Danishefsky SJ

    更新日期:1998-12-22 00:00:00