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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
Öppna denna publikation i ny flik eller fönster >>Inhibition of Nuclear PTEN Tyrosine Phosphorylation Enhances Glioma diation Sensitivity through Attenuated DNA Repair
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2019 (Engelska)Ingår i: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 35, nr 3, s. 504-518.e7Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Cell Press, 2019
Nationell ämneskategori
Farmakologi och toxikologi
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)
Anmärkning

QC 20190503

Tillgänglig från: 2019-05-03 Skapad: 2019-05-03 Senast uppdaterad: 2019-05-03Bibliografiskt granskad
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
Öppna denna publikation i ny flik eller fönster >>Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope
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2019 (Engelska)Ingår 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. 10009-10018Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
NATL ACAD SCIENCES, 2019
Nyckelord
cancer, mutational heterogeneity, structural convergence, intermediate, cryptoepitope
Nationell ämneskategori
Klinisk medicin
Identifikatorer
urn:nbn:se:kth:diva-252604 (URN)10.1073/pnas.1821442116 (DOI)000467804000052 ()31028138 (PubMedID)2-s2.0-85065738222 (Scopus ID)
Anmärkning

QC 20190610

Tillgänglig från: 2019-06-10 Skapad: 2019-06-10 Senast uppdaterad: 2019-06-10Bibliografiskt granskad
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.
Öppna denna publikation i ny flik eller fönster >>Ten simple rules on how to create open access and reproducible molecular simulations of biological systems
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2019 (Engelska)Ingår i: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 15, nr 1, artikel-id e1006649Artikel i tidskrift, Editorial material (Övrigt vetenskapligt) Published
Ort, förlag, år, upplaga, sidor
PUBLIC LIBRARY SCIENCE, 2019
Nationell ämneskategori
Bioinformatik (beräkningsbiologi)
Identifikatorer
urn:nbn:se:kth:diva-244559 (URN)10.1371/journal.pcbi.1006649 (DOI)000457372500019 ()30653494 (PubMedID)2-s2.0-85060780890 (Scopus ID)
Anmärkning

QC 20190312

Tillgänglig från: 2019-03-12 Skapad: 2019-03-12 Senast uppdaterad: 2019-03-12Bibliografiskt granskad
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
Öppna denna publikation i ny flik eller fönster >>ALCOHOL MODULATION VIA ALLOSTERIC TRANSMEMBRANE SITES IN PENTAMERIC LIGAND-GATED ION CHANNELS
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2018 (Engelska)Ingår i: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 42, s. 60A-60AArtikel i tidskrift, Meeting abstract (Refereegranskat) Published
Ort, förlag, år, upplaga, sidor
Wiley, 2018
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:kth:diva-235138 (URN)000443221300188 ()
Konferens
19th World Congress of International-Society-for-Biomedical-Research-on-Alcoholism (ISBRA), SEP 09-13, 2018, Kyoto, JAPAN
Anmärkning

QC 20180920

Tillgänglig från: 2018-09-20 Skapad: 2018-09-20 Senast uppdaterad: 2018-09-20Bibliografiskt granskad
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
Öppna denna publikation i ny flik eller fönster >>Allosteric potentiation of a ligand-gated ion channel is mediated by access to a deep membrane-facing cavity
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2018 (Engelska)Ingår 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. 10672-10677Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
NATL ACAD SCIENCES, 2018
Nyckelord
ion channels, molecular dynamics, oocyte, general anesthetic, allostery
Nationell ämneskategori
Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
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
Anmärkning

QC 20181120

Tillgänglig från: 2018-11-20 Skapad: 2018-11-20 Senast uppdaterad: 2018-11-20Bibliografiskt granskad
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.
Öppna denna publikation i ny flik eller fönster >>Characterisation of molecular motions in cryo-EM single-particle data by multi-body refinement in RELION
2018 (Engelska)Ingår i: eLIFE, E-ISSN 2050-084X, Vol. 7, artikel-id e36861Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
ELIFE SCIENCES PUBLICATIONS LTD, 2018
Nationell ämneskategori
Mediateknik
Identifikatorer
urn:nbn:se:kth:diva-231720 (URN)10.7554/eLife.36861 (DOI)000435436100001 ()29856314 (PubMedID)2-s2.0-85051994136 (Scopus ID)
Anmärkning

QC 20180817

Tillgänglig från: 2018-08-17 Skapad: 2018-08-17 Senast uppdaterad: 2018-11-13Bibliografiskt granskad
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
Öppna denna publikation i ny flik eller fönster >>Determining the molecular basis of voltage sensitivity in membrane proteins
2018 (Engelska)Ingår i: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 215, nr 10, s. 1444-1458Artikel i tidskrift (Refereegranskat) 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. 

Ort, förlag, år, upplaga, sidor
Rockefeller University Press, 2018
Nationell ämneskategori
Fysik
Identifikatorer
urn:nbn:se:kth:diva-236661 (URN)10.1085/jgp.201812086 (DOI)000447673900012 ()2-s2.0-85054072236 (Scopus ID)
Forskningsfinansiär
Vetenskapsrådet, 2017-04641Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Anmärkning

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

Tillgänglig från: 2018-11-13 Skapad: 2018-11-13 Senast uppdaterad: 2018-11-13Bibliografiskt granskad
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
Öppna denna publikation i ny flik eller fönster >>Expansion of a Transmembrane Cavity Facilitates Anesthetic Potentiation of a Pentameric Ligand Gated Ion Channel
2018 (Engelska)Ingår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 114, nr 3, s. 299A-299AArtikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Ort, förlag, år, upplaga, sidor
CELL PRESS, 2018
Nationell ämneskategori
Biofysik
Identifikatorer
urn:nbn:se:kth:diva-228291 (URN)000430450000015 ()
Konferens
62nd Annual Meeting of the Biophysical-Society, FEB 17-21, 2018, San Francisco, CA
Anmärkning

QC 20180521

Tillgänglig från: 2018-05-21 Skapad: 2018-05-21 Senast uppdaterad: 2018-05-21Bibliografiskt granskad
Narangifard, A., den Hollander, L., Wennberg, C. L., Lundborg, M., Lindahl, E., Iwai, I., . . . Norlen, L. (2018). Human skin barrier formation takes place via a cubic to lamellar lipid phase transition as analyzed by cryo-electron microscopy and EM-simulation. Experimental Cell Research, 366(2), 139-151
Öppna denna publikation i ny flik eller fönster >>Human skin barrier formation takes place via a cubic to lamellar lipid phase transition as analyzed by cryo-electron microscopy and EM-simulation
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2018 (Engelska)Ingår i: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 366, nr 2, s. 139-151Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The skin's permeability barrier consists of stacked lipid sheets of splayed ceramides, cholesterol and free fatty acids, positioned intercellularly in the stratum corneum. We report here on the early stage of skin barrier formation taking place inside the tubuloreticular system in the secretory cells of the topmost viable epidermis and in the intercellular space between viable epidermis and stratum corneum. The barrier formation process was analysed in situ in its near-native state, using cryo-EM combined with molecular dynamics modeling and EM simulation. Stacks of lamellae appear towards the periphery of the tubuloreticular system and they are closely associated with granular regions. Only models based on a bicontinuous cubic phase organization proved compatible with the granular cryo-EM patterns. Only models based on a dehydrated lamellar phase organization agreed with the lamellar cryo-EM patterns. The data support that human skin barrier formation takes place via a cubic to lamellar lipid phase transition.

Ort, förlag, år, upplaga, sidor
Elsevier, 2018
Nyckelord
Cryo-EM, EM simulation, Skin barrier formation, Molecular dynamics
Nationell ämneskategori
Cancer och onkologi Cellbiologi
Identifikatorer
urn:nbn:se:kth:diva-226737 (URN)10.1016/j.yexcr.2018.03.010 (DOI)000429630100007 ()29567114 (PubMedID)2-s2.0-85044525984 (Scopus ID)
Forskningsfinansiär
The Wenner-Gren FoundationVetenskapsrådetScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Anmärkning

QC 20180522

Tillgänglig från: 2018-05-22 Skapad: 2018-05-22 Senast uppdaterad: 2018-05-22Bibliografiskt granskad
Lundborg, M., Narangifard, A., Wennberg, C. L., Lindahl, E., Daneholt, B. & Norlén, L. (2018). Human skin barrier structure and function analyzed by cryo-EM and molecular dynamics simulation. Journal of Structural Biology, 203(2), 149-161
Öppna denna publikation i ny flik eller fönster >>Human skin barrier structure and function analyzed by cryo-EM and molecular dynamics simulation
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2018 (Engelska)Ingår i: Journal of Structural Biology, ISSN 1047-8477, E-ISSN 1095-8657, Vol. 203, nr 2, s. 149-161Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

In the present study we have analyzed the molecular structure and function of the human skin's permeability barrier using molecular dynamics simulation validated against cryo-electron microscopy data from near native skin. The skin's barrier capacity is located to an intercellular lipid structure embedding the cells of the superficial most layer of skin - the stratum corneum. According to the splayed bilayer model (Iwai et al., 2012) the lipid structure is organized as stacked bilayers of ceramides in a splayed chain conformation with cholesterol associated with the ceramide sphingoid moiety and free fatty acids associated with the ceramide fatty acid moiety. However, knowledge about the lipid structure's detailed molecular organization, and the roles of its different lipid constituents, remains circumstantial. Starting from a molecular dynamics model based on the splayed bilayer model, we have, by stepwise structural and compositional modifications, arrived at a thermodynamically stable molecular dynamics model expressing simulated electron microscopy patterns matching original cryo-electron microscopy patterns from skin extremely closely. Strikingly, the closer the individual molecular dynamics models' lipid composition was to that reported in human stratum corneum, the better was the match between the models' simulated electron microscopy patterns and the original cryo-electron microscopy patterns. Moreover, the closest-matching model's calculated water permeability and thermotropic behaviour were found compatible with that of human skin. The new model may facilitate more advanced physics-based skin permeability predictions of drugs and toxicants. The proposed procedure for molecular dynamics based analysis of cellular cryo-electron microscopy data might be applied to other biomolecular systems.

Ort, förlag, år, upplaga, sidor
Academic Press, 2018
Nyckelord
Stratum corneum, Skin permeation, Cryo-EM, Molecular dynamics simulation, Lipids
Nationell ämneskategori
Biokemi och molekylärbiologi
Identifikatorer
urn:nbn:se:kth:diva-232599 (URN)10.1016/j.jsb.2018.04.005 (DOI)000437807900010 ()29702212 (PubMedID)2-s2.0-85046730207 (Scopus ID)
Forskningsfinansiär
VetenskapsrådetWenner-Gren StiftelsernaSvenska läkaresällskapetSwedish e‐Science Research Center
Anmärkning

QC 20180731

Tillgänglig från: 2018-07-31 Skapad: 2018-07-31 Senast uppdaterad: 2018-07-31Bibliografiskt granskad
Organisationer
Identifikatorer
ORCID-id: ORCID iD iconorcid.org/0000-0002-2734-2794

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