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Publications (10 of 133) Show all publications
Gharpure, A., Teng, J., Zhuang, Y., Noviello, C. M., Walsh, R. M. ., Cabuco, R., . . . Hibbs, R. E. (2019). Agonist Selectivity and Ion Permeation in the alpha 3 beta 4 Ganglionic Nicotinic Receptor. Neuron, 104(3), 501-+
Open this publication in new window or tab >>Agonist Selectivity and Ion Permeation in the alpha 3 beta 4 Ganglionic Nicotinic Receptor
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2019 (English)In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 104, no 3, p. 501-+Article in journal (Refereed) Published
Abstract [en]

Nicotinic acetylcholine receptors are pentameric ion channels that mediate fast chemical neurotransmission. The alpha 3 beta 4 nicotinic receptor subtype forms the principal relay between the central and peripheral nervous systems in the autonomic ganglia. This receptor is also expressed focally in brain areas that affect reward circuits and addiction. Here, we present structures of the alpha 3 beta 4 nicotinic receptor in lipidic and detergent environments, using functional reconstitution to define lipids appropriate for structural analysis. The structures of the receptor in complex with nicotine, as well as the alpha 3 beta 4-selective ligand AT-1001, complemented by molecular dynamics, suggest principles of agonist selectivity. The structures further reveal much of the architecture of the intracellular domain, where mutagenesis experiments and simulations define residues governing ion conductance.

Place, publisher, year, edition, pages
CELL PRESS, 2019
National Category
Basic Medicine
Identifiers
urn:nbn:se:kth:diva-264322 (URN)10.1016/j.neuron.2019.07.030 (DOI)000495107500012 ()31488329 (PubMedID)2-s2.0-85074236074 (Scopus ID)
Note

QC 20191202

Available from: 2019-12-02 Created: 2019-12-02 Last updated: 2019-12-02Bibliographically approved
Orellana, L., Gustavsson, J., Bergh, C., Yoluk, O. & Lindahl, E. (2019). eBDIMS server: protein transition pathways with ensemble analysis in 2D-motion spaces. Bioinformatics, 35(18), 3505-3507
Open this publication in new window or tab >>eBDIMS server: protein transition pathways with ensemble analysis in 2D-motion spaces
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2019 (English)In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 35, no 18, p. 3505-3507Article in journal (Refereed) Published
Abstract [en]

A Summary: Understanding how proteins transition between different conformers, and how conformers relate to each other in terms of structure and function, is not trivial. Here, we present an online tool for transition pathway generation between two protein conformations using Elastic Network Driven Brownian Dynamics Importance Sampling, a coarse-grained simulation algorithm, which spontaneously predicts transition intermediates trapped experimentally. In addition to path-generation, the server provides an interactive 2D-motion landscape graphical representation of the transitions or any additional conformers to explore their structural relationships.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2019
National Category
Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:kth:diva-261959 (URN)10.1093/bioinformatics/btz104 (DOI)000487327500044 ()30838394 (PubMedID)2-s2.0-85065714382 (Scopus ID)
Note

QC 20191015

Available from: 2019-10-15 Created: 2019-10-15 Last updated: 2019-10-15Bibliographically approved
Ma, J., Benite, J. A., Miki, S., Albuquerqu, C. P., Galatro, T., Orellana, L., . . . Furnari, F. B. (2019). Inhibition of Nuclear PTEN Tyrosine Phosphorylation Enhances Glioma diation Sensitivity through Attenuated DNA Repair. Cancer Cell, 35(3), 504-518.e7
Open this publication in new window or tab >>Inhibition of Nuclear PTEN Tyrosine Phosphorylation Enhances Glioma diation Sensitivity through Attenuated DNA Repair
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2019 (English)In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 35, no 3, p. 504-518.e7Article in journal (Refereed) Published
Abstract [en]

Ionizing radiation (IR) and chemotherapy are standard-of-care treatments for glioblastoma (GBM) patients and both result in DNA damage, however, the clinical efficacy is limited due to therapeutic resistance. We identified a mechanism of such resistance mediated by phosphorylation of PTEN on tyrosine 240 (pY240-PTEN) by FGFR2. pY240-PTEN is rapidly elevated and bound to chromatin through interaction with Ki-67 in response to IR treatment and facilitates the recruitment of RAD51 to promote DNA repair. Blocking Y240 phosphorylation confers radiation sensitivity to tumors and extends survival in GBM preclinical models. Y240F-Pten knockin mice showed radiation sensitivity. These results suggest that FGFR-mediated pY240-PTEN is a key mechanism of radiation resistance and is an actionable target for improving radiotherapy efficacy.

Place, publisher, year, edition, pages
Cell Press, 2019
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:kth:diva-248334 (URN)10.1016/j.ccell.2019.01.020 (DOI)000461697400015 ()30827889 (PubMedID)2-s2.0-85062686655 (Scopus ID)
Note

QC 20190503

Available from: 2019-05-03 Created: 2019-05-03 Last updated: 2019-05-03Bibliographically approved
Orellana, L., Thorne, A. H., Lema, R., Gustavsson, J., Parisian, A. D., Hospital, A., . . . Orozco, M. (2019). Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope. Proceedings of the National Academy of Sciences of the United States of America, 116(20), 10009-10018
Open this publication in new window or tab >>Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope
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2019 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 20, p. 10009-10018Article in journal (Refereed) Published
Abstract [en]

Epidermal growth factor receptor (EGFR) signaling is initiated by a large ligand-favored conformational change of the extracellular domain (ECD) from a closed, self-inhibited tethered monomer, to an open untethered state, which exposes a loop required for strong dimerization and activation. In glioblastomas (GBMs), structurally heterogeneous missense and deletion mutations concentrate at the ECD for unclear reasons. We explore the conformational impact of GBM missense mutations, combining elastic network models (ENMs) with multiple molecular dynamics (MD) trajectories. Our simulations reveal that the main missense class, located at the I-II interface away from the self-inhibitory tether, can unexpectedly favor spontaneous untethering to a compact intermediate state, here validated by small-angle X-ray scattering (SAXS). Significantly, such intermediate is characterized by the rotation of a large ECD fragment (N-TR1), deleted in the most common GBM mutation, EGFRvIII, and that makes accessible a cryptic epitope characteristic of cancer cells. This observation suggested potential structural equivalence of missense and deletion ECD changes in GBMs. Corroborating this hypothesis, our FACS, in vitro, and in vivo data demonstrate that entirely different ECD variants all converge to remove N-TR1 steric hindrance from the 806-epitope, which we show is allosterically coupled to an intermediate kinase and hallmarks increased oncogenicity. Finally, the detected extraintracellular coupling allows for synergistic cotargeting of the intermediate with mAb806 and inhibitors, which is proved herein.

Place, publisher, year, edition, pages
NATL ACAD SCIENCES, 2019
Keywords
cancer, mutational heterogeneity, structural convergence, intermediate, cryptoepitope
National Category
Clinical Medicine
Identifiers
urn:nbn:se:kth:diva-252604 (URN)10.1073/pnas.1821442116 (DOI)000467804000052 ()31028138 (PubMedID)2-s2.0-85065738222 (Scopus ID)
Note

QC 20190610

Available from: 2019-06-10 Created: 2019-06-10 Last updated: 2019-06-10Bibliographically approved
Elofsson, A., Hess, B., Lindahl, E., Onufriev, A., van der Spoel, D. & Wallqvist, A. (2019). Ten simple rules on how to create open access and reproducible molecular simulations of biological systems. PloS Computational Biology, 15(1), Article ID e1006649.
Open this publication in new window or tab >>Ten simple rules on how to create open access and reproducible molecular simulations of biological systems
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2019 (English)In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 15, no 1, article id e1006649Article in journal, Editorial material (Other academic) Published
Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2019
National Category
Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:kth:diva-244559 (URN)10.1371/journal.pcbi.1006649 (DOI)000457372500019 ()30653494 (PubMedID)2-s2.0-85060780890 (Scopus ID)
Note

QC 20190312

Available from: 2019-03-12 Created: 2019-03-12 Last updated: 2019-03-12Bibliographically approved
Howard, R. J., Heusser, S. A., Zhuang, Y., Lycksell, M., Klement, G., Orellana, L. & Lindahl, E. (2018). ALCOHOL MODULATION VIA ALLOSTERIC TRANSMEMBRANE SITES IN PENTAMERIC LIGAND-GATED ION CHANNELS. Paper presented at 19th World Congress of International-Society-for-Biomedical-Research-on-Alcoholism (ISBRA), SEP 09-13, 2018, Kyoto, JAPAN. Alcoholism: Clinical and Experimental Research, 42, 60A-60A
Open this publication in new window or tab >>ALCOHOL MODULATION VIA ALLOSTERIC TRANSMEMBRANE SITES IN PENTAMERIC LIGAND-GATED ION CHANNELS
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2018 (English)In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 42, p. 60A-60AArticle in journal, Meeting abstract (Refereed) Published
Place, publisher, year, edition, pages
Wiley, 2018
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:kth:diva-235138 (URN)000443221300188 ()
Conference
19th World Congress of International-Society-for-Biomedical-Research-on-Alcoholism (ISBRA), SEP 09-13, 2018, Kyoto, JAPAN
Note

QC 20180920

Available from: 2018-09-20 Created: 2018-09-20 Last updated: 2018-09-20Bibliographically approved
Heusser, S. A., Lycksell, M., Wang, X., McComas, S. E., Howard, R. J. & Lindahl, E. (2018). Allosteric potentiation of a ligand-gated ion channel is mediated by access to a deep membrane-facing cavity. Proceedings of the National Academy of Sciences of the United States of America, 115(42), 10672-10677
Open this publication in new window or tab >>Allosteric potentiation of a ligand-gated ion channel is mediated by access to a deep membrane-facing cavity
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2018 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 42, p. 10672-10677Article in journal (Refereed) Published
Abstract [en]

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 similar 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.

Place, publisher, year, edition, pages
NATL ACAD SCIENCES, 2018
Keywords
ion channels, molecular dynamics, oocyte, general anesthetic, allostery
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:kth:diva-238118 (URN)10.1073/pnas.1809650115 (DOI)000447491300054 ()30275330 (PubMedID)2-s2.0-85054997177 (Scopus ID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20181120

Available from: 2018-11-20 Created: 2018-11-20 Last updated: 2018-11-20Bibliographically approved
Nakane, T., Kimanius, D., Lindahl, E. & Scheres, S. H. W. (2018). Characterisation of molecular motions in cryo-EM single-particle data by multi-body refinement in RELION. eLIFE, 7, Article ID e36861.
Open this publication in new window or tab >>Characterisation of molecular motions in cryo-EM single-particle data by multi-body refinement in RELION
2018 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 7, article id e36861Article in journal (Refereed) Published
Abstract [en]

Macromolecular complexes that exhibit continuous forms of structural flexibility pose a challenge for many existing tools in cryo-EM single-particle analysis. We describe a new tool, called multi-body refinement, which models flexible complexes as a user-defined number of rigid bodies that move independently from each other. Using separate focused refinements with iteratively improved partial signal subtraction, the new tool generates improved reconstructions for each of the defined bodies in a fully automated manner. Moreover, using principal component analysis on the relative orientations of the bodies over all particle images in the data set, we generate movies that describe the most important motions in the data. Our results on two test cases, a cytoplasmic ribosome from Plasmodium falciparum, and the spliceosomal B-complex from yeast, illustrate how multi-body refinement can be useful to gain unique insights into the structure and dynamics of large and flexible macromolecular complexes.

Place, publisher, year, edition, pages
ELIFE SCIENCES PUBLICATIONS LTD, 2018
National Category
Media Engineering
Identifiers
urn:nbn:se:kth:diva-231720 (URN)10.7554/eLife.36861 (DOI)000435436100001 ()29856314 (PubMedID)2-s2.0-85051994136 (Scopus ID)
Note

QC 20180817

Available from: 2018-08-17 Created: 2018-08-17 Last updated: 2018-11-13Bibliographically approved
Kasimova, M. A., Lindahl, E. & Delemotte, L. (2018). Determining the molecular basis of voltage sensitivity in membrane proteins. The Journal of General Physiology, 215(10), 1444-1458
Open this publication in new window or tab >>Determining the molecular basis of voltage sensitivity in membrane proteins
2018 (English)In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 215, no 10, p. 1444-1458Article in journal (Refereed) Published
Abstract [en]

Voltage-sensitive membrane proteins are united by their ability to transform changes in membrane potential into mechanical work. They are responsible for a spectrum of physiological processes in living organisms, including electrical signaling and cell-cycle progression. Although the mechanism of voltage-sensing has been well characterized for some membrane proteins, including voltage-gated ion channels, even the location of the voltage-sensing elements remains unknown for others. Moreover, the detection of these elements by using experimental techniques is challenging because of the diversity of membrane proteins. Here, we provide a computational approach to predict voltage-sensing elements in any membrane protein, independent of its structure or function. It relies on an estimation of the propensity of a protein to respond to changes in membrane potential. We first show that this property correlates well with voltage sensitivity by applying our approach to a set of voltage-sensitive and voltage-insensitive membrane proteins. We further show that it correctly identifies authentic voltage-sensitive residues in the voltage-sensor domain of voltage-gated ion channels. Finally, we investigate six membrane proteins for which the voltage-sensing elements have not yet been characterized and identify residues and ions that might be involved in the response to voltage. The suggested approach is fast and simple and enables a characterization of voltage sensitivity that goes beyond mere identification of charges. We anticipate that its application before mutagenesis experiments will significantly reduce the number of potential voltage-sensitive elements to be tested. 

Place, publisher, year, edition, pages
Rockefeller University Press, 2018
National Category
Physical Sciences
Identifiers
urn:nbn:se:kth:diva-236661 (URN)10.1085/jgp.201812086 (DOI)000447673900012 ()2-s2.0-85054072236 (Scopus ID)
Funder
Swedish Research Council, 2017-04641Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

Export Date: 22 October 2018; Article; CODEN: JGPLA; Correspondence Address: Delemotte, L.; Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of TechnologySweden; email: lucie.delemotte@scilifelab.se. QC 20181113

Available from: 2018-11-13 Created: 2018-11-13 Last updated: 2018-11-13Bibliographically approved
Eriksson, O., Laure, E., Lindahl, E., Henningson, D. S. & Ynnerman, A. (2018). e-Science in Scandinavia. Informatik-Spektrum, 41(6), 398-404
Open this publication in new window or tab >>e-Science in Scandinavia
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2018 (English)In: Informatik-Spektrum, ISSN 0170-6012, E-ISSN 1432-122X, Vol. 41, no 6, p. 398-404Article in journal (Refereed) Published
National Category
Computer and Information Sciences
Identifiers
urn:nbn:se:kth:diva-260432 (URN)10.1007/s00287-018-01133-2 (DOI)2-s2.0-85058461975 (Scopus ID)
Note

QC 20191011

Available from: 2019-09-30 Created: 2019-09-30 Last updated: 2019-10-11Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-2734-2794

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