Change search
Link to record
Permanent link

Direct link
BETA
Alternative names
Publications (10 of 19) Show all publications
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
Show others...
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
Howard, R. J., Heusser, S. A., Yoluk, O., Snow, O., Klement, G., Mola, A. R., . . . Lindahl, E. (2017). Transmembrane Structural Determinants of Alcohol Binding and Modulation in a Model Ligand-Gated Ion Channel. Paper presented at 58th Annual Meeting of the Biophysical-Society, FEB 15-19, 2014, San Francisco, CA. Biophysical Journal, 112(3), 554A-554A
Open this publication in new window or tab >>Transmembrane Structural Determinants of Alcohol Binding and Modulation in a Model Ligand-Gated Ion Channel
Show others...
2017 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 112, no 3, p. 554A-554AArticle in journal (Refereed) Published
Place, publisher, year, edition, pages
CELL PRESS, 2017
National Category
Biophysics
Identifiers
urn:nbn:se:kth:diva-210511 (URN)10.1016/j.bpj.2016.11.2988 (DOI)000402375700756 ()
Conference
58th Annual Meeting of the Biophysical-Society, FEB 15-19, 2014, San Francisco, CA
Note

QC 20170704

Available from: 2017-07-04 Created: 2017-07-04 Last updated: 2017-07-04Bibliographically approved
Yoluk, Ö. (2016). Elucidating the Gating Mechanism of Cys-Loop Receptors. (Doctoral dissertation). Stockholm: KTH Royal Institute of Technology
Open this publication in new window or tab >>Elucidating the Gating Mechanism of Cys-Loop Receptors
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cys-loop receptors are membrane proteins that are key players for the fast synaptic neurotransmission. Their ion transport initiates new nerve signals after activation by small agonist molecules, but this function is also highly sensitive to allosteric modulation by a number of compounds such as anesthetics, alcohol or anti-parasitic agents. For a long time, these modulators were believed to act primarily on the membrane, but the availability of high- resolution structures has made it possible to identify several binding sites in the transmembrane domains of the ion channels. It is known that ligand binding in the extracellular domain causes a conformational earthquake that interacts with the transmembrane domain, which leads to channel opening. The investigations carried out in this thesis aim at understanding the connection between ligand binding and channel opening.

I present new models of the mammalian GABAA receptor based on the eukaryotic structure GluCl co-crystallized with an anti-parasitic agent, and show how these models can be used to study receptor-modulator interactions. I also show how removal of the bound modulator leads to gradual closing of the channel in molecular dynamics simulations. In contrast, simulations of the receptor with both the agonist and the modulator remain stable in an open-like conformation. This makes it possible to extract several key interactions, and I propose mechanisms for how the extracellular domain motion is initiated. The rapid increase in the number of cys-loop receptor structures the last few years has further made it possible to use principal component analysis (PCA) to create low-dimensional descriptions of the conformational landscape. By performing PCA on the crystal structure ensemble, I have been able to divide the structures into functional clusters and sample the transitions between them using various sampling methods.

The studies presented in this thesis contribute to our understanding of the gating mechanism and the functional clustering of the cys-loop receptor structures, which both are important to design new allosteric modulator drugs that influence the channel function, in particular to treat neurological disorders.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2016. p. 72
Series
TRITA-FYS, ISSN 0280-316X ; 2016:26
Keywords
ion channel, gating, simulation, molecular dynamics, receptor, cys-loop, modelling
National Category
Biophysics
Research subject
Theoretical Chemistry and Biology; Biological Physics
Identifiers
urn:nbn:se:kth:diva-187230 (URN)978-91-7729-009-4 (ISBN)
Public defence
2016-06-13, sal F3, Lindstedtsvägen 26, Stockholm, 14:00 (English)
Opponent
Supervisors
Note

QC 20160518

Available from: 2016-05-18 Created: 2016-05-18 Last updated: 2016-05-20Bibliographically approved
Heusser, S., Yoluk, Ö., Klement, G., Reiderer, E., Lindahl, E. & Howard, R. (2016). Functional Characterization of Neurotransmitter Activation and Modulation in a Nematode Model Ligand-gated Ion Channel. Journal of Neurochemistry, 138(2), 243-253
Open this publication in new window or tab >>Functional Characterization of Neurotransmitter Activation and Modulation in a Nematode Model Ligand-gated Ion Channel
Show others...
2016 (English)In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 138, no 2, p. 243-253Article in journal (Refereed) Published
Abstract [en]

The superfamily of pentameric ligand-gated ion channels includes neurotransmitter receptors that mediate fast synaptic transmission in vertebrates, and are targets for drugs including alcohols, anesthetics, benzodiazepines and anticonvulsants. However, the mechanisms of ion channel opening, gating and modulation in these receptors leave many open questions, despite their pharmacological importance. Subtle conformational changes in both the extracellular and transmembrane domains are likely to influence channel opening, but have been difficult to characterize given the limited structural data available for human membrane proteins. Recent crystal structures of a modifiedCaenorhabditis elegans glutamate-gated chloride channel (GluCl) in multiple states offer an appealing model system for structure-function studies. However, the pharmacology of the crystallographic GluCl construct is not well established. To establish the functional relevance of this system, we used two-electrode voltage-clamp electrophysiology in Xenopus oocytes to characterize activation of crystallographic and native-like GluCl constructs by L-glutamate and ivermectin. We also tested modulation by ethanol and other anesthetic agents, and used site-directed mutagenesis to explore the role of a region of Loop F which was implicated in ligand gating by molecular dynamics simulations. Our findings indicate that the crystallographic construct functionally models concentration-dependent agonism and allosteric modulation of pharmacologically relevant receptors. Specific substitutions at residue Leu174 in loop F altered direct L-glutamate activation, consistent with computational evidence for this region's role in ligand binding. These insights demonstrate conservation of activation and modulation properties in this receptor family, and establish a framework for GluCl as a model system, including new possibilities for drug discovery.

Place, publisher, year, edition, pages
John Wiley & Sons, 2016
Keywords
anesthetic, cys-loop receptor, GluCl, Ion channel, pLGIC
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-187250 (URN)10.1111/jnc.13644 (DOI)000380263700004 ()27102368 (PubMedID)2-s2.0-84979036020 (Scopus ID)
External cooperation:
Funder
Swedish Research Council, 2013-5901Swedish e‐Science Research Center
Note

QC 20160518

Available from: 2016-05-18 Created: 2016-05-18 Last updated: 2017-11-30Bibliographically approved
Orellana, L., Yoluk, Ö., Carrillo, O., Orozco, M. & Lindahl, E. (2016). Prediction and Validation of Protein Intermediate States from Structurally Rich Ensembles and Coarse-Grained Simulations. Nature Communications, 7
Open this publication in new window or tab >>Prediction and Validation of Protein Intermediate States from Structurally Rich Ensembles and Coarse-Grained Simulations
Show others...
2016 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7Article in journal (Refereed) Published
Abstract [en]

Protein conformational changes are at the heart of cell functions, from signaling to ion transport. However, the transient nature of the intermediates along transition pathways hampers their experimental detection, making the underlying mechanisms elusive. Here, we retrieve dynamic information on the actual transition routes from Principal Component Analysis (PCA) of structurally-rich ensembles and, in combination with coarse-grained simulations, explore the conformational landscapes of five well-studied proteins. Modeling them as elastic networks in a hybrid Elastic-Network Brownian Dynamics simulation (eBDIMS), we generate trajectories connecting stable end-states that spontaneously sample the crystallographic motions, predicting the structures of known intermediates along thepaths. We also show that the explored non-linear routes can delimit the lowest energy passages between end-states sampled by atomistic molecular dynamics. The integrative methodology presented here provides a powerful framework to extract and expand dynamic pathway information from the Protein Data Bank, as well as to validate sampling methods in general. 

Place, publisher, year, edition, pages
Nature Publishing Group, 2016
National Category
Structural Biology
Identifiers
urn:nbn:se:kth:diva-187252 (URN)10.1038/ncomms12575 (DOI)000391870700001 ()2-s2.0-84984943375 (Scopus ID)
Note

QC 20160518

Available from: 2016-05-18 Created: 2016-05-18 Last updated: 2018-12-05Bibliographically approved
Yoluk, Ö., Orellana, L., Bertaccini, E. J., Trudell, J. R. & Lindahl, E. (2016). Principal Components from Ligand-Gated Ion Channel Structures Enable Ensemble Studies of Microsecond-Scale Transitions. Paper presented at 60th Annual Meeting of the Biophysical-Society, FEB 27-MAR 02, 2016, Los Angeles, CA. Biophysical Journal, 110(3), 454A-454A
Open this publication in new window or tab >>Principal Components from Ligand-Gated Ion Channel Structures Enable Ensemble Studies of Microsecond-Scale Transitions
Show others...
2016 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 110, no 3, p. 454A-454AArticle in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Cell Press, 2016
National Category
Biophysics
Identifiers
urn:nbn:se:kth:diva-187846 (URN)000375142700206 ()
Conference
60th Annual Meeting of the Biophysical-Society, FEB 27-MAR 02, 2016, Los Angeles, CA
Note

QC 20160531

Available from: 2016-05-31 Created: 2016-05-30 Last updated: 2017-11-30Bibliographically approved
Nys, M., Farinha, A., Wijckmans, E., Brams, M., Yoluk, Ö., Andersson, M., . . . Ulens, C. (2016). The Crystal Structure of ELIC in Complex with Chlorpromazine Unexpectedly Unveils an Allosteric Binding Site in the Ligand-Binding Domain. Paper presented at 60th Annual Meeting of the Biophysical-Society, FEB 27-MAR 02, 2016, Los Angeles, CA. Biophysical Journal, 110(3), 457A-457A
Open this publication in new window or tab >>The Crystal Structure of ELIC in Complex with Chlorpromazine Unexpectedly Unveils an Allosteric Binding Site in the Ligand-Binding Domain
Show others...
2016 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 110, no 3, p. 457A-457AArticle in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Cell Press, 2016
National Category
Biophysics
Identifiers
urn:nbn:se:kth:diva-187848 (URN)000375142700221 ()
Conference
60th Annual Meeting of the Biophysical-Society, FEB 27-MAR 02, 2016, Los Angeles, CA
Note

QC 20160530

Available from: 2016-05-30 Created: 2016-05-30 Last updated: 2017-11-30Bibliographically approved
Yoluk, O., Lindahl, E. & Andersson, M. (2015). Conformational Gating Dynamics in the GluCl Anion-Selective Chloride Channel. ACS Chemical Neuroscience, 6(8), 1459-1467
Open this publication in new window or tab >>Conformational Gating Dynamics in the GluCl Anion-Selective Chloride Channel
2015 (English)In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 6, no 8, p. 1459-1467Article in journal (Refereed) Published
Abstract [en]

Cys-loop receptors are central to propagation of signals in the nervous system. The gating of the membrane-spanning pore is triggered by structural rearrangements in the agonist-binding site, located some so A away from the pore. A sequential conformational change, propagating from the ligand-binding site to the pore, has been proposed to govern gating in all Cys-loop receptors. Here, we identify structural and dynamic components of the conformational gating in the eukaryotic glutamate-gated chloride channel (GluCl) by means of molecular dynamics (MD) simulations with and without the L-glutamate agonist bound. A significant increase in pore opening and accompanying hydration is observed in the presence of glutamate. Potential of mean force calculations reveal that the barrier for ion passage drops from 15 kcal/mol to 5-10 kcal/mol with the agonist bound. This appears to be explained by agonist binding that leads to significant changes in the intersubunit hydrogen-bonding pattern, which induce a slight tilt of the extracellular domain relative to the transmembrane domain in the simulations. This rearrangement is subtle, but correspond to the direction of the quaternary twist observed as a key difference between open and closed X-ray structures. While the full reversible gating is still a much slower process, the observed structural dynamics sheds new light on the early stages of how the agonist influences the extracellular domain, how the extracellular domain interacts with the transmembrane domain, and how changes in the transmembrane domain alter the free energy of ion passage.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2015
Keywords
Membrane protein, ligand-gated ion channel, cys-loop receptor, molecular dynamics simulations
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-173445 (URN)10.1021/acschemneuro.5b00111 (DOI)000359967300022 ()25992588 (PubMedID)2-s2.0-84939864190 (Scopus ID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20171128

Available from: 2015-09-18 Created: 2015-09-11 Last updated: 2017-11-28Bibliographically approved
Heusser, S. A., Yoluk, O. & Lindahl, E. (2015). Exploring the Gating Pathway in an Eukaryotic Ligand-Gated Ion Channel. Paper presented at 59th Annual Meeting of the Biophysical-Society, FEB 07-11, 2015, Baltimore, MD. Biophysical Journal, 108(2), 433A-433A
Open this publication in new window or tab >>Exploring the Gating Pathway in an Eukaryotic Ligand-Gated Ion Channel
2015 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 108, no 2, p. 433A-433AArticle in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
CELL PRESS, 2015
National Category
Biophysics
Identifiers
urn:nbn:se:kth:diva-243705 (URN)10.1016/j.bpj.2014.11.2365 (DOI)000362849400591 ()
Conference
59th Annual Meeting of the Biophysical-Society, FEB 07-11, 2015, Baltimore, MD
Note

QC 20190227

Available from: 2019-02-27 Created: 2019-02-27 Last updated: 2019-04-09Bibliographically approved
Yoluk, O., Heusser, S., Andersson, M., Orellana, L. & Lindahl, E. (2015). Gating Ritual: Simulations of Gating in Glutamate-Gated Chloride Channel. Paper presented at 59th Annual Meeting of the Biophysical-Society, FEB 07-11, 2015, Baltimore, MD. Biophysical Journal, 108(2), 431A-431A
Open this publication in new window or tab >>Gating Ritual: Simulations of Gating in Glutamate-Gated Chloride Channel
Show others...
2015 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 108, no 2, p. 431A-431AArticle in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
CELL PRESS, 2015
National Category
Biophysics
Identifiers
urn:nbn:se:kth:diva-243704 (URN)000362849400581 ()
Conference
59th Annual Meeting of the Biophysical-Society, FEB 07-11, 2015, Baltimore, MD
Note

QC 20180227

Available from: 2019-02-27 Created: 2019-02-27 Last updated: 2019-05-22Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-8354-0253

Search in DiVA

Show all publications