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Publications (10 of 136) Show all publications
Howard, R. J., Zhuang, Y., Heusser, S. A., Bergh, C., Rovsnik, U., Orellana, L. & Lindahl, E. (2020). Allosteric Gating Determinants in the Transmembrane Domain of Pentameric Ligand-Gated Ion Channels. Paper presented at 64th Annual Meeting of the Biophysical-Society, FEB 15-19, 2020, San Diego, CA. Biophysical Journal, 118(3), 584A-584A
Open this publication in new window or tab >>Allosteric Gating Determinants in the Transmembrane Domain of Pentameric Ligand-Gated Ion Channels
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2020 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 118, no 3, p. 584A-584AArticle in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
CELL PRESS, 2020
Identifiers
urn:nbn:se:kth:diva-271299 (URN)000513023203654 ()
Conference
64th Annual Meeting of the Biophysical-Society, FEB 15-19, 2020, San Diego, CA
Note

QC 20200402

Available from: 2020-04-02 Created: 2020-04-02 Last updated: 2020-04-02Bibliographically approved
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: 2019-12-19Bibliographically 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
Abraham, M. J., Apostolov, R., Barnoud, J., Bauer, P., Blau, C., Bonvin, A. M. J., . . . Zhmurov, A. (2019). Sharing Data from Molecular Simulations. Journal of Chemical Information and Modeling, 59(10), 4093-4099
Open this publication in new window or tab >>Sharing Data from Molecular Simulations
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2019 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 59, no 10, p. 4093-4099Article in journal (Refereed) Published
Abstract [en]

Given the need for modern researchers to produce open, reproducible scientific output, the lack of standards and best practices for sharing data and workflows used to produce and analyze molecular dynamics (MD) simulations has become an important issue in the field. There are now multiple well-established packages to perform molecular dynamics simulations, often highly tuned for exploiting specific classes of hardware, each with strong communities surrounding them, but with very limited interoperability/transferability options. Thus, the choice of the software package often dictates the workflow for both simulation production and analysis. The level of detail in documenting the workflows and analysis code varies greatly in published work, hindering reproducibility of the reported results and the ability for other researchers to build on these studies. An increasing number of researchers are motivated to make their data available, but many challenges remain in order to effectively share and reuse simulation data. To discuss these and other issues related to best practices in the field in general, we organized a workshop in November 2018 (https://bioexcel.eu/events/workshop-on-sharing-data-from-molecular-simulations/). Here, we present a brief overview of this workshop and topics discussed. We hope this effort will spark further conversation in the MD community to pave the way toward more open, interoperable, and reproducible outputs coming from research studies using MD simulations.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2019
National Category
Software Engineering
Identifiers
urn:nbn:se:kth:diva-266543 (URN)10.1021/acs.jcim.9b00665 (DOI)000503918200007 ()31525920 (PubMedID)2-s2.0-85073732839 (Scopus ID)
Note

QC 20200131

Available from: 2020-01-31 Created: 2020-01-31 Last updated: 2020-01-31Bibliographically 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-s2.0-85060153842 (Scopus ID)
Note

QC 20190312

Available from: 2019-03-12 Created: 2019-03-12 Last updated: 2020-03-05Bibliographically approved
Bergh, C., Orellana, L., Howard, R. J. & Lindahl, E. (2019). Understanding the Conformational Dynamics of a Pentameric Ligand-Gated Ion Channel through Markov State Modeling. Paper presented at 63rd Annual Meeting of the Biophysical-Society, MAR 02-06, 2019, Baltimore, MD. Biophysical Journal, 116(3), 395A-396A
Open this publication in new window or tab >>Understanding the Conformational Dynamics of a Pentameric Ligand-Gated Ion Channel through Markov State Modeling
2019 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 116, no 3, p. 395A-396AArticle in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Cell Press, 2019
National Category
Biophysics
Identifiers
urn:nbn:se:kth:diva-270633 (URN)10.1016/j.bpj.2018.11.2138 (DOI)000460779801971 ()
Conference
63rd Annual Meeting of the Biophysical-Society, MAR 02-06, 2019, Baltimore, MD
Note

QC 20200311

Available from: 2020-03-11 Created: 2020-03-11 Last updated: 2020-03-11Bibliographically 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
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-2734-2794

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