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Publikasjoner (10 av 132) Visa alla publikasjoner
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
Åpne denne publikasjonen i ny fane eller vindu >>eBDIMS server: protein transition pathways with ensemble analysis in 2D-motion spaces
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2019 (engelsk)Inngår i: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 35, nr 18, s. 3505-3507Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
OXFORD UNIV PRESS, 2019
HSV kategori
Identifikatorer
urn:nbn:se:kth:diva-261959 (URN)10.1093/bioinformatics/btz104 (DOI)000487327500044 ()30838394 (PubMedID)2-s2.0-85065714382 (Scopus ID)
Merknad

QC 20191015

Tilgjengelig fra: 2019-10-15 Laget: 2019-10-15 Sist oppdatert: 2019-10-15bibliografisk kontrollert
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
Åpne denne publikasjonen i ny fane eller vindu >>Inhibition of Nuclear PTEN Tyrosine Phosphorylation Enhances Glioma diation Sensitivity through Attenuated DNA Repair
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2019 (engelsk)Inngår i: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 35, nr 3, s. 504-518.e7Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
Cell Press, 2019
HSV kategori
Identifikatorer
urn:nbn:se:kth:diva-248334 (URN)10.1016/j.ccell.2019.01.020 (DOI)000461697400015 ()30827889 (PubMedID)2-s2.0-85062686655 (Scopus ID)
Merknad

QC 20190503

Tilgjengelig fra: 2019-05-03 Laget: 2019-05-03 Sist oppdatert: 2019-05-03bibliografisk kontrollert
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
Åpne denne publikasjonen i ny fane eller vindu >>Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope
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2019 (engelsk)Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, nr 20, s. 10009-10018Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
NATL ACAD SCIENCES, 2019
Emneord
cancer, mutational heterogeneity, structural convergence, intermediate, cryptoepitope
HSV kategori
Identifikatorer
urn:nbn:se:kth:diva-252604 (URN)10.1073/pnas.1821442116 (DOI)000467804000052 ()31028138 (PubMedID)2-s2.0-85065738222 (Scopus ID)
Merknad

QC 20190610

Tilgjengelig fra: 2019-06-10 Laget: 2019-06-10 Sist oppdatert: 2019-06-10bibliografisk kontrollert
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.
Åpne denne publikasjonen i ny fane eller vindu >>Ten simple rules on how to create open access and reproducible molecular simulations of biological systems
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2019 (engelsk)Inngår i: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 15, nr 1, artikkel-id e1006649Artikkel i tidsskrift, Editorial material (Annet vitenskapelig) Published
sted, utgiver, år, opplag, sider
PUBLIC LIBRARY SCIENCE, 2019
HSV kategori
Identifikatorer
urn:nbn:se:kth:diva-244559 (URN)10.1371/journal.pcbi.1006649 (DOI)000457372500019 ()30653494 (PubMedID)2-s2.0-85060780890 (Scopus ID)
Merknad

QC 20190312

Tilgjengelig fra: 2019-03-12 Laget: 2019-03-12 Sist oppdatert: 2019-03-12bibliografisk kontrollert
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
Åpne denne publikasjonen i ny fane eller vindu >>ALCOHOL MODULATION VIA ALLOSTERIC TRANSMEMBRANE SITES IN PENTAMERIC LIGAND-GATED ION CHANNELS
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2018 (engelsk)Inngår i: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 42, s. 60A-60AArtikkel i tidsskrift, Meeting abstract (Fagfellevurdert) Published
sted, utgiver, år, opplag, sider
Wiley, 2018
HSV kategori
Identifikatorer
urn:nbn:se:kth:diva-235138 (URN)000443221300188 ()
Konferanse
19th World Congress of International-Society-for-Biomedical-Research-on-Alcoholism (ISBRA), SEP 09-13, 2018, Kyoto, JAPAN
Merknad

QC 20180920

Tilgjengelig fra: 2018-09-20 Laget: 2018-09-20 Sist oppdatert: 2018-09-20bibliografisk kontrollert
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
Åpne denne publikasjonen i ny fane eller vindu >>Allosteric potentiation of a ligand-gated ion channel is mediated by access to a deep membrane-facing cavity
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2018 (engelsk)Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, nr 42, s. 10672-10677Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
NATL ACAD SCIENCES, 2018
Emneord
ion channels, molecular dynamics, oocyte, general anesthetic, allostery
HSV kategori
Identifikatorer
urn:nbn:se:kth:diva-238118 (URN)10.1073/pnas.1809650115 (DOI)000447491300054 ()30275330 (PubMedID)2-s2.0-85054997177 (Scopus ID)
Forskningsfinansiär
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Merknad

QC 20181120

Tilgjengelig fra: 2018-11-20 Laget: 2018-11-20 Sist oppdatert: 2018-11-20bibliografisk kontrollert
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.
Åpne denne publikasjonen i ny fane eller vindu >>Characterisation of molecular motions in cryo-EM single-particle data by multi-body refinement in RELION
2018 (engelsk)Inngår i: eLIFE, E-ISSN 2050-084X, Vol. 7, artikkel-id e36861Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
ELIFE SCIENCES PUBLICATIONS LTD, 2018
HSV kategori
Identifikatorer
urn:nbn:se:kth:diva-231720 (URN)10.7554/eLife.36861 (DOI)000435436100001 ()29856314 (PubMedID)2-s2.0-85051994136 (Scopus ID)
Merknad

QC 20180817

Tilgjengelig fra: 2018-08-17 Laget: 2018-08-17 Sist oppdatert: 2018-11-13bibliografisk kontrollert
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
Åpne denne publikasjonen i ny fane eller vindu >>Determining the molecular basis of voltage sensitivity in membrane proteins
2018 (engelsk)Inngår i: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 215, nr 10, s. 1444-1458Artikkel i tidsskrift (Fagfellevurdert) 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. 

sted, utgiver, år, opplag, sider
Rockefeller University Press, 2018
HSV kategori
Identifikatorer
urn:nbn:se:kth:diva-236661 (URN)10.1085/jgp.201812086 (DOI)000447673900012 ()2-s2.0-85054072236 (Scopus ID)
Forskningsfinansiär
Swedish Research Council, 2017-04641Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Merknad

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

Tilgjengelig fra: 2018-11-13 Laget: 2018-11-13 Sist oppdatert: 2018-11-13bibliografisk kontrollert
Eriksson, O., Laure, E., Lindahl, E., Henningson, D. S. & Ynnerman, A. (2018). e-Science in Scandinavia. Informatik-Spektrum, 41(6), 398-404
Åpne denne publikasjonen i ny fane eller vindu >>e-Science in Scandinavia
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2018 (engelsk)Inngår i: Informatik-Spektrum, ISSN 0170-6012, E-ISSN 1432-122X, Vol. 41, nr 6, s. 398-404Artikkel i tidsskrift (Fagfellevurdert) Published
HSV kategori
Identifikatorer
urn:nbn:se:kth:diva-260432 (URN)10.1007/s00287-018-01133-2 (DOI)2-s2.0-85058461975 (Scopus ID)
Merknad

QC 20191011

Tilgjengelig fra: 2019-09-30 Laget: 2019-09-30 Sist oppdatert: 2019-10-11bibliografisk kontrollert
Lycksell, M., Heusser, S. A., Howard, R. J. & Lindahl, E. (2018). Expansion of a Transmembrane Cavity Facilitates Anesthetic Potentiation of a Pentameric Ligand Gated Ion Channel. Paper presented at 62nd Annual Meeting of the Biophysical-Society, FEB 17-21, 2018, San Francisco, CA. Biophysical Journal, 114(3), 299A-299A
Åpne denne publikasjonen i ny fane eller vindu >>Expansion of a Transmembrane Cavity Facilitates Anesthetic Potentiation of a Pentameric Ligand Gated Ion Channel
2018 (engelsk)Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 114, nr 3, s. 299A-299AArtikkel i tidsskrift, Meeting abstract (Annet vitenskapelig) Published
sted, utgiver, år, opplag, sider
CELL PRESS, 2018
HSV kategori
Identifikatorer
urn:nbn:se:kth:diva-228291 (URN)000430450000015 ()
Konferanse
62nd Annual Meeting of the Biophysical-Society, FEB 17-21, 2018, San Francisco, CA
Merknad

QC 20180521

Tilgjengelig fra: 2018-05-21 Laget: 2018-05-21 Sist oppdatert: 2018-05-21bibliografisk kontrollert
Organisasjoner
Identifikatorer
ORCID-id: ORCID iD iconorcid.org/0000-0002-2734-2794