Conformational Dynamics on the Extracellular Side of LeuT Controlled by Na + and K + Ions and the Protonation State of Glu 290

Khelashvili, George; Schmidt, Solveig Gaarde; Shi, Lei; Javitch, Jonathan A.; Gether, Ulrik; Loland, Claus J.; Weinstein, Harel

doi:10.1074/jbc.m116.731455

Conformational Dynamics on the Extracellular Side of LeuT Controlled by Na ⁺ and K ⁺ Ions and the Protonation State of Glu ²⁹⁰

Journal Article · Fri Jul 29 00:00:00 EDT 2016 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.m116.731455· OSTI ID:1565483

Khelashvili, George ^[1]; Schmidt, Solveig Gaarde ^[2]; Shi, Lei ^[3]; Javitch, Jonathan A. ^[4]; Gether, Ulrik ^[2]; Loland, Claus J. ^[2]; Weinstein, Harel ^[1]

Cornell Univ., Ithaca, NY (United States)
Univ. of Copenhagen (Denmark)
Cornell Univ., Ithaca, NY (United States); National Inst. of Health (NIH), Baltimore, MD (United States)
Columbia Univ., New York, NY (United States); New York State Psychiatric Inst., New York, NY (United States)

Ions play key mechanistic roles in the gating dynamics of neurotransmitter:sodium symporters (NSSs). In other microsecond scale molecular dynamics simulations of a complete model of the dopamine transporter, a NSS protein, we observed a partitioning of K⁺ ions from the intracellular side toward the unoccupied Na2 site of dopamine transporter following the release of the Na2-bound Na⁺. In this work, we evaluate with computational simulations and experimental measurements of ion affinities under corresponding conditions, the consequences of K+ binding in the Na2 site of LeuT, a bacterial homolog of NSS, when both Na⁺ ions and substrate have left, and the transporter prepares for a new cycle. We compare the results with the consequences of binding Na⁺ in the same apo system. Analysis of >50-μs atomistic molecular dynamics and enhanced sampling trajectories of constructs with Glu²⁹⁰, either charged or neutral, point to the Glu²⁹⁰ protonation state as a main determinant in the structural reconfiguration of the extracellular vestibule of LeuT in which a “water gate” opens through coordinated motions of residues Leu²⁵, Tyr¹⁰⁸, and Phe²⁵³. The resulting water channel allows the binding/dissociation of the Na⁺ and K⁺ ions that are prevalent, respectively, in the extracellular and intracellular environments.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF)

Sponsoring Organization:: USDOE Office of Science

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1565483

Journal Information:: Journal of Biological Chemistry, Journal Name: Journal of Biological Chemistry Journal Issue: 38 Vol. 291; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: English

References (77)

Scalable molecular dynamics with NAMD Phillips, James C.; Braun, Rosemary; Wang, Wei Journal of Computational Chemistry, Vol. 26, Issue 16, p. 1781-1802 https://doi.org/10.1002/jcc.20289	journal	January 2005
Computational modeling of the N-terminus of the human dopamine transporter and its interaction with PIP ₂ -containing membranes : Modeling of DAT N-Terminus/PIP Khelashvili, George; Doktorova, Milka; Sahai, Michelle A. Proteins: Structure, Function, and Bioinformatics, Vol. 83, Issue 5 https://doi.org/10.1002/prot.24792	journal	March 2015
Synaptic uptake and beyond: the sodium- and chloride-dependent neurotransmitter transporter family SLC6 Chen, Nian-Hang; Reith, Maarten E. A.; Quick, Michael W. Pfl�gers Archiv European Journal of Physiology, Vol. 447, Issue 5 https://doi.org/10.1007/s00424-003-1064-5	journal	February 2004
A Closer Look at Amphetamine-Induced Reverse Transport and Trafficking of the Dopamine and Norepinephrine Transporters Robertson, S. D.; Matthies, H. J. G.; Galli, A. Molecular Neurobiology, Vol. 39, Issue 2 https://doi.org/10.1007/s12035-009-8053-4	journal	February 2009
VMD: Visual molecular dynamics Humphrey, William; Dalke, Andrew; Schulten, Klaus Journal of Molecular Graphics, Vol. 14, Issue 1 https://doi.org/10.1016/0263-7855(96)00018-5	journal	February 1996
Monoamine Transporter as a Target Molecule for Psychostimulants Sora, Ichiro; Li, BingJin; Fumushima, Setsu International Review of Neurobiology https://doi.org/10.1016/S0074-7742(09)85003-4	book	January 2009
Computational approaches to detect allosteric pathways in transmembrane molecular machines Stolzenberg, Sebastian; Michino, Mayako; LeVine, Michael V. Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1858, Issue 7 https://doi.org/10.1016/j.bbamem.2016.01.010	journal	July 2016
CHARMM-GUI Membrane Builder for Mixed Bilayers and Its Application to Yeast Membranes Jo, Sunhwan; Lim, Joseph B.; Klauda, Jeffery B. Biophysical Journal, Vol. 97, Issue 1 https://doi.org/10.1016/j.bpj.2009.04.013	journal	July 2009
Ion-Releasing State of a Secondary Membrane Transporter Li, Jing; Tajkhorshid, Emad Biophysical Journal, Vol. 97, Issue 11 https://doi.org/10.1016/j.bpj.2009.09.005	journal	December 2009
Ion-Controlled Conformational Dynamics in the Outward-Open Transition from an Occluded State of LeuT Zhao, Chunfeng; Stolzenberg, Sebastian; Gracia, Luis Biophysical Journal, Vol. 103, Issue 5 https://doi.org/10.1016/j.bpj.2012.07.044	journal	September 2012
Coupled Global and Local Changes Direct Substrate Translocation by Neurotransmitter-Sodium Symporter Ortholog LeuT Cheng, Mary Hongying; Bahar, Ivet Biophysical Journal, Vol. 105, Issue 3 https://doi.org/10.1016/j.bpj.2013.06.032	journal	August 2013
Spontaneous Inward Opening of the Dopamine Transporter is Triggered by PIP2-Regulated Dynamics of the N-Terminus Khelashvili, George; Stanley, Nathaniel; Sahai, Michelle Biophysical Journal, Vol. 110, Issue 3 https://doi.org/10.1016/j.bpj.2015.11.3354	journal	February 2016
The cost of living in the membrane: A case study of hydrophobic mismatch for the multi-segment protein LeuT Mondal, Sayan; Khelashvili, George; Shi, Lei Chemistry and Physics of Lipids, Vol. 169 https://doi.org/10.1016/j.chemphyslip.2013.01.006	journal	April 2013
The Mechanism of a Neurotransmitter:Sodium Symporter—Inward Release of Na+ and Substrate Is Triggered by Substrate in a Second Binding Site Shi, Lei; Quick, Matthias; Zhao, Yongfang Molecular Cell, Vol. 30, Issue 6 https://doi.org/10.1016/j.molcel.2008.05.008	journal	June 2008
Mechanisms of neurotransmitter release by amphetamines: A review Sulzer, David; Sonders, Mark S.; Poulsen, Nathan W. Progress in Neurobiology, Vol. 75, Issue 6 https://doi.org/10.1016/j.pneurobio.2005.04.003	journal	April 2005
Role of Annular Lipids in the Functional Properties of Leucine Transporter LeuT Proteomicelles LeVine, Michael V.; Khelashvili, George; Shi, Lei Biochemistry, Vol. 55, Issue 6 https://doi.org/10.1021/acs.biochem.5b01268	journal	February 2016
Allosteric Mechanisms of Molecular Machines at the Membrane: Transport by Sodium-Coupled Symporters LeVine, Michael V.; Cuendet, Michel A.; Khelashvili, George Chemical Reviews, Vol. 116, Issue 11 https://doi.org/10.1021/acs.chemrev.5b00627	journal	February 2016
Spontaneous Inward Opening of the Dopamine Transporter Is Triggered by PIP ₂ -Regulated Dynamics of the N-Terminus Khelashvili, George; Stanley, Nathaniel; Sahai, Michelle A. ACS Chemical Neuroscience, Vol. 6, Issue 11 https://doi.org/10.1021/acschemneuro.5b00179	journal	August 2015
The Role of Local Hydration and Hydrogen-Bonding Dynamics in Ion and Solute Release from Ion-Coupled Secondary Transporters Zhao, Chunfeng; Noskov, Sergei Yu. Biochemistry, Vol. 50, Issue 11 https://doi.org/10.1021/bi101454f	journal	March 2011
Sodium-Coupled Neurotransmitter Transporters Kanner, Baruch I.; Zomot, Elia Chemical Reviews, Vol. 108, Issue 5 https://doi.org/10.1021/cr078246a	journal	May 2008
PROPKA3: Consistent Treatment of Internal and Surface Residues in Empirical p K _a Predictions Olsson, Mats H. M.; Søndergaard, Chresten R.; Rostkowski, Michal Journal of Chemical Theory and Computation, Vol. 7, Issue 2 https://doi.org/10.1021/ct100578z	journal	December 2010
Optimization of the Additive CHARMM All-Atom Protein Force Field Targeting Improved Sampling of the Backbone ϕ, ψ and Side-Chain χ ₁ and χ ₂ Dihedral Angles Best, Robert B.; Zhu, Xiao; Shim, Jihyun Journal of Chemical Theory and Computation, Vol. 8, Issue 9 https://doi.org/10.1021/ct300400x	journal	August 2012
ACEMD: Accelerating Biomolecular Dynamics in the Microsecond Time Scale Harvey, M. J.; Giupponi, G.; Fabritiis, G. De Journal of Chemical Theory and Computation, Vol. 5, Issue 6 https://doi.org/10.1021/ct9000685	journal	May 2009
The Membrane Protein LeuT in Micellar Systems: Aggregation Dynamics and Detergent Binding to the S2 Site Khelashvili, George; LeVine, Michael V.; Shi, Lei Journal of the American Chemical Society, Vol. 135, Issue 38 https://doi.org/10.1021/ja405984v	journal	September 2013
Update of the CHARMM All-Atom Additive Force Field for Lipids: Validation on Six Lipid Types Klauda, Jeffery B.; Venable, Richard M.; Freites, J. Alfredo The Journal of Physical Chemistry B, Vol. 114, Issue 23 https://doi.org/10.1021/jp101759q	journal	June 2010
Molecular Simulations of Dodecyl-β-maltoside Micelles in Water: Influence of the Headgroup Conformation and Force Field Parameters Abel, Stéphane; Dupradeau, François-Yves; Raman, E. Prabhu The Journal of Physical Chemistry B, Vol. 115, Issue 3 https://doi.org/10.1021/jp109545v	journal	January 2011
Simulations of Anionic Lipid Membranes: Development of Interaction-Specific Ion Parameters and Validation Using NMR Data Venable, Richard M.; Luo, Yun; Gawrisch, Klaus The Journal of Physical Chemistry B, Vol. 117, Issue 35 https://doi.org/10.1021/jp401512z	journal	August 2013
Insights into transport mechanism from LeuT engineered to transport tryptophan: Insights into transport mechanism Piscitelli, Chayne L.; Gouaux, Eric The EMBO Journal, Vol. 31, Issue 1 https://doi.org/10.1038/emboj.2011.353	journal	September 2011
Substrate binds in the S1 site of the F253A mutant of LeuT, a neurotransmitter sodium symporter homologue Wang, Hui; Gouaux, Eric EMBO reports, Vol. 13, Issue 9 https://doi.org/10.1038/embor.2012.110	journal	July 2012
Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters Yamashita, Atsuko; Singh, Satinder K.; Kawate, Toshimitsu Nature, Vol. 437, Issue 7056 https://doi.org/10.1038/nature03978	journal	July 2005
Antidepressant binding site in a bacterial homologue of neurotransmitter transporters Singh, Satinder K.; Yamashita, Atsuko; Gouaux, Eric Nature, Vol. 448, Issue 7156 https://doi.org/10.1038/nature06038	journal	August 2007
Mechanism of chloride interaction with neurotransmitter:sodium symporters Zomot, Elia; Bendahan, Annie; Quick, Matthias Nature, Vol. 449, Issue 7163 https://doi.org/10.1038/nature06133	journal	August 2007
Single-molecule dynamics of gating in a neurotransmitter transporter homologue Zhao, Yongfang; Terry, Daniel; Shi, Lei Nature, Vol. 465, Issue 7295 https://doi.org/10.1038/nature09057	journal	May 2010
Neurotransmitter/sodium symporter orthologue LeuT has a single high-affinity substrate site Piscitelli, Chayne L.; Krishnamurthy, Harini; Gouaux, Eric Nature, Vol. 468, Issue 7327 https://doi.org/10.1038/nature09581	journal	December 2010
Substrate-modulated gating dynamics in a Na+-coupled neurotransmitter transporter homologue Zhao, Yongfang; Terry, Daniel S.; Shi, Lei Nature, Vol. 474, Issue 7349 https://doi.org/10.1038/nature09971	journal	April 2011
X-ray structures of LeuT in substrate-free outward-open and apo inward-open states Krishnamurthy, Harini; Gouaux, Eric Nature, Vol. 481, Issue 7382 https://doi.org/10.1038/nature10737	journal	January 2012
X-ray structure of dopamine transporter elucidates antidepressant mechanism Penmatsa, Aravind; Wang, Kevin H.; Gouaux, Eric Nature, Vol. 503, Issue 7474 https://doi.org/10.1038/nature12533	journal	September 2013
Substrate-dependent proton antiport in neurotransmitter:sodium symporters Zhao, Yongfang; Quick, Matthias; Shi, Lei Nature Chemical Biology, Vol. 6, Issue 2 https://doi.org/10.1038/nchembio.284	journal	December 2009
A conserved leucine occupies the empty substrate site of LeuT in the Na+-free return state Malinauskaite, Lina; Said, Saida; Sahin, Caglanur Nature Communications, Vol. 7, Issue 1 https://doi.org/10.1038/ncomms11673	journal	May 2016
The binding sites for cocaine and dopamine in the dopamine transporter overlap Beuming, Thijs; Kniazeff, Julie; Bergmann, Marianne L. Nature Neuroscience, Vol. 11, Issue 7 https://doi.org/10.1038/nn.2146	journal	June 2008
Plasma membrane monoamine transporters: structure, regulation and function Torres, Gonzalo E.; Gainetdinov, Raul R.; Caron, Marc G. Nature Reviews Neuroscience, Vol. 4, Issue 1 https://doi.org/10.1038/nrn1008	journal	January 2003
Ion/substrate-dependent conformational dynamics of a bacterial homolog of neurotransmitter:sodium symporters Claxton, Derek P.; Quick, Matthias; Shi, Lei Nature Structural & Molecular Biology, Vol. 17, Issue 7 https://doi.org/10.1038/nsmb.1854	journal	June 2010
Experimental conditions can obscure the second high-affinity site in LeuT Quick, Matthias; Shi, Lei; Zehnpfennig, Britta Nature Structural & Molecular Biology, Vol. 19, Issue 2 https://doi.org/10.1038/nsmb.2197	journal	January 2012
Structures of LeuT in bicelles define conformation and substrate binding in a membrane-like context Wang, Hui; Elferich, Johannes; Gouaux, Eric Nature Structural & Molecular Biology, Vol. 19, Issue 2 https://doi.org/10.1038/nsmb.2215	journal	January 2012
Conformational dynamics of ligand-dependent alternating access in LeuT Kazmier, Kelli; Sharma, Shruti; Quick, Matthias Nature Structural & Molecular Biology, Vol. 21, Issue 5 https://doi.org/10.1038/nsmb.2816	journal	April 2014
X-ray structures of Drosophila dopamine transporter in complex with nisoxetine and reboxetine Penmatsa, Aravind; Wang, Kevin H.; Gouaux, Eric Nature Structural & Molecular Biology, Vol. 22, Issue 6 https://doi.org/10.1038/nsmb.3029	journal	May 2015
One-dimensional intergrowths in two-dimensional zeolite nanosheets and their effect on ultra-selective transport Kumar, Prashant; Kim, Dae Woo; Rangnekar, Neel Nature Materials, Vol. 19, Issue 4 https://doi.org/10.1038/s41563-019-0581-3	journal	February 2020
Nosé–Hoover chains: The canonical ensemble via continuous dynamics Martyna, Glenn J.; Klein, Michael L.; Tuckerman, Mark The Journal of Chemical Physics, Vol. 97, Issue 4 https://doi.org/10.1063/1.463940	journal	August 1992
A smooth particle mesh Ewald method Essmann, Ulrich; Perera, Lalith; Berkowitz, Max L. The Journal of Chemical Physics, Vol. 103, Issue 19 https://doi.org/10.1063/1.470117	journal	November 1995
Monitoring the function of membrane transport proteins in detergent-solubilized form Quick, M.; Javitch, J. A. Proceedings of the National Academy of Sciences, Vol. 104, Issue 9 https://doi.org/10.1073/pnas.0609573104	journal	February 2007
Binding of an octylglucoside detergent molecule in the second substrate (S2) site of LeuT establishes an inhibitor-bound conformation Quick, M.; Winther, A. -M. L.; Shi, L. Proceedings of the National Academy of Sciences, Vol. 106, Issue 14 https://doi.org/10.1073/pnas.0811322106	journal	March 2009
Transient formation of water-conducting states in membrane transporters Li, J.; Shaikh, S. A.; Enkavi, G. Proceedings of the National Academy of Sciences, Vol. 110, Issue 19 https://doi.org/10.1073/pnas.1218986110	journal	April 2013
Chloride binding site of neurotransmitter sodium symporters Kantcheva, A. K.; Quick, M.; Shi, L. Proceedings of the National Academy of Sciences, Vol. 110, Issue 21 https://doi.org/10.1073/pnas.1221279110	journal	May 2013
Conformational cycle and ion-coupling mechanism of the Na+/hydantoin transporter Mhp1 Kazmier, K.; Sharma, S.; Islam, S. M. Proceedings of the National Academy of Sciences, Vol. 111, Issue 41 https://doi.org/10.1073/pnas.1410431111	journal	September 2014
Octopamine mediates starvation-induced hyperactivity in adult Drosophila Yang, Zhe; Yu, Yue; Zhang, Vivian Proceedings of the National Academy of Sciences, Vol. 112, Issue 16 https://doi.org/10.1073/pnas.1417838112	journal	April 2015
Reconstructing a Chloride-binding Site in a Bacterial Neurotransmitter Transporter Homologue Tavoulari, Sotiria; Rizwan, Ahsan N.; Forrest, Lucy R. Journal of Biological Chemistry, Vol. 286, Issue 4 https://doi.org/10.1074/jbc.M110.186064	journal	November 2010
The Second Sodium Site in the Dopamine Transporter Controls Cation Permeation and Is Regulated by Chloride Borre, Lars; Andreassen, Thorvald F.; Shi, Lei Journal of Biological Chemistry, Vol. 289, Issue 37 https://doi.org/10.1074/jbc.M114.574269	journal	July 2014
Microseconds Simulations Reveal a New Sodium-binding Site and the Mechanism of Sodium-coupled Substrate Uptake by LeuT Zomot, Elia; Gur, Mert; Bahar, Ivet Journal of Biological Chemistry, Vol. 290, Issue 1 https://doi.org/10.1074/jbc.M114.617555	journal	November 2014
Mechanism of the Association between Na ⁺ Binding and Conformations at the Intracellular Gate in Neurotransmitter:Sodium Symporters Stolzenberg, Sebastian; Quick, Matthias; Zhao, Chunfeng Journal of Biological Chemistry, Vol. 290, Issue 22 https://doi.org/10.1074/jbc.M114.625343	journal	April 2015
Substrate-induced Unlocking of the Inner Gate Determines the Catalytic Efficiency of a Neurotransmitter:Sodium Symporter Billesbølle, Christian B.; Krüger, Mie B.; Shi, Lei Journal of Biological Chemistry, Vol. 290, Issue 44 https://doi.org/10.1074/jbc.M115.677658	journal	September 2015
An Intracellular Interaction Network Regulates Conformational Transitions in the Dopamine Transporter Kniazeff, Julie; Shi, Lei; Loland, Claus J. Journal of Biological Chemistry, Vol. 283, Issue 25 https://doi.org/10.1074/jbc.M800475200	journal	April 2008
Canonical dynamics: Equilibrium phase-space distributions Hoover, William G. Physical Review A, Vol. 31, Issue 3 https://doi.org/10.1103/PhysRevA.31.1695	journal	March 1985
The solute carrier 6 family of transporters: The Solute Carrier Family 6 Bröer, Stefan; Gether, Ulrik British Journal of Pharmacology, Vol. 167, Issue 2 https://doi.org/10.1111/j.1476-5381.2012.01975.x	journal	August 2012
How LeuT shapes our understanding of the mechanisms of sodium-coupled neurotransmitter transporters: Role of LeuT in understanding neurotransmitter transporters Penmatsa, Aravind; Gouaux, Eric The Journal of Physiology, Vol. 592, Issue 5 https://doi.org/10.1113/jphysiol.2013.259051	journal	August 2013
A Juxtamembrane Mutation in the N Terminus of the Dopamine Transporter Induces Preference for an Inward-Facing Conformation Guptaroy, Bipasha; Zhang, Minjia; Bowton, Erica Molecular Pharmacology, Vol. 75, Issue 3 https://doi.org/10.1124/mol.108.048744	journal	December 2008
A Competitive Inhibitor Traps LeuT in an Open-to-Out Conformation Singh, S. K.; Piscitelli, C. L.; Yamashita, A. Science, Vol. 322, Issue 5908 https://doi.org/10.1126/science.1166777	journal	December 2008
Anton, a special-purpose machine for molecular dynamics simulation Shaw, David E.; Chao, Jack C.; Eastwood, Michael P. Proceedings of the 34th annual international symposium on Computer architecture - ISCA '07 https://doi.org/10.1145/1250662.1250664	conference	January 2007
Anton, a special-purpose machine for molecular dynamics simulation Shaw, David E.; Chao, Jack C.; Eastwood, Michael P. ACM SIGARCH Computer Architecture News, Vol. 35, Issue 2 https://doi.org/10.1145/1273440.1250664	journal	June 2007
Anton, a special-purpose machine for molecular dynamics simulation Shaw, David E.; Chao, Jack C.; Eastwood, Michael P. Communications of the ACM, Vol. 51, Issue 7 https://doi.org/10.1145/1364782.1364802	journal	July 2008
Modeling and Dynamics of the Inward-Facing State of a Na+/Cl− Dependent Neurotransmitter Transporter Homologue Shaikh, Saher Afshan; Tajkhorshid, Emad PLoS Computational Biology, Vol. 6, Issue 8 https://doi.org/10.1371/journal.pcbi.1000905	journal	August 2010
Mutational Analysis of the High-Affinity Zinc Binding Site Validates a Refined Human Dopamine Transporter Homology Model Stockner, Thomas; Montgomery, Therese R.; Kudlacek, Oliver PLoS Computational Biology, Vol. 9, Issue 2 https://doi.org/10.1371/journal.pcbi.1002909	journal	February 2013
The Molecular Mechanism of Ion-Dependent Gating in Secondary Transporters Zhao, Chunfeng; Noskov, Sergei Yu. PLoS Computational Biology, Vol. 9, Issue 10 https://doi.org/10.1371/journal.pcbi.1003296	journal	October 2013
NbIT - A New Information Theory-Based Analysis of Allosteric Mechanisms Reveals Residues that Underlie Function in the Leucine Transporter LeuT LeVine, Michael V.; Weinstein, Harel PLoS Computational Biology, Vol. 10, Issue 5 https://doi.org/10.1371/journal.pcbi.1003603	journal	May 2014
Complete Mapping of Substrate Translocation Highlights the Role of LeuT N-terminal Segment in Regulating Transport Cycle Cheng, Mary Hongying; Bahar, Ivet PLoS Computational Biology, Vol. 10, Issue 10 https://doi.org/10.1371/journal.pcbi.1003879	journal	October 2014
The Substrate-Driven Transition to an Inward-Facing Conformation in the Functional Mechanism of the Dopamine Transporter Shan, Jufang; Javitch, Jonathan A.; Shi, Lei PLoS ONE, Vol. 6, Issue 1 https://doi.org/10.1371/journal.pone.0016350	journal	January 2011
Ligand Induced Conformational Changes of the Human Serotonin Transporter Revealed by Molecular Dynamics Simulations Koldsø, Heidi; Autzen, Henriette Elisabeth; Grouleff, Julie PLoS ONE, Vol. 8, Issue 6 https://doi.org/10.1371/journal.pone.0063635	journal	June 2013
Substrate Binding and Formation of an Occluded State in the Leucine Transporter Celik, Leyla; Schiøtt, Birgit; Tajkhorshid, Emad Biophysical Journal, Vol. 94, Issue 5 https://doi.org/10.1529/biophysj.107.117580	journal	March 2008

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A kinetic account for amphetamine-induced monoamine release Hasenhuetl, Peter S.; Bhat, Shreyas; Mayer, Felix P. Journal of General Physiology, Vol. 150, Issue 3 https://doi.org/10.1085/jgp.201711915	journal	February 2018
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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
conformational change
membrane protein
molecular dynamics
monoamine transporter
neurotransmitter transport