Structural Mechanism of N-Methyl-D-Aspartate Receptor Type 1 Partial Agonism
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{"title"=>"Structural Mechanism of N-Methyl-D-Aspartate Receptor Type 1 Partial Agonism", "type"=>"journal", "authors"=>[{"first_name"=>"Mikko", "last_name"=>"Ylilauri", "scopus_author_id"=>"42862713900"}, {"first_name"=>"Olli T.", "last_name"=>"Pentikäinen", "scopus_author_id"=>"6602134444"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84867497048", "doi"=>"10.1371/journal.pone.0047604", "pui"=>"365864406", "pmid"=>"23077649", "scopus"=>"2-s2.0-84867497048", "issn"=>"19326203"}, "id"=>"19437eb0-7fa3-33be-ac1d-8ee33bc78217", "abstract"=>"N-methyl-D-aspartate (NMDA) receptors belong to a family of ionotropic glutamate receptors that contribute to the signal transmission in the central nervous system. NMDA receptors are heterotetramers that usually consist of two GluN1 and GluN2 monomers. The extracellular ligand-binding domain (LBD) of a monomer is comprised of discontinuous segments that form the functional domains D1 and D2. While the binding of a full agonist glycine to LBD of GluN1 is linked to cleft closure and subsequent ion-channel opening, partial agonists are known to activate the receptor only sub-maximally. Although the crystal structures of the LBD of related GluA2 receptor explain the mechanism for the partial agonism, structures of GluN1-LBD cannot distinguish the difference between full and partial agonists. It is, however, probable that the partial agonists of GluN1 alter the structure of the LBD in order to result in a different pharmacological response than seen with full agonists. In this study, we used molecular dynamics simulations to reveal an intermediate closure-stage for GluN1, which is unseen in crystal structures. According to our calculations, this intermediate closure is not a transient stage but an energetically stable conformation. Our results demonstrate that the partial agonist cannot exert firm GluN1-LBD closure, especially if there is even a small force that disrupts the LBD closure. Accordingly, this result suggests the importance of forces from the ion channel for the relationship between pharmacological response and the structure of the LBD of members of this receptor family.", "link"=>"http://www.mendeley.com/research/structural-mechanism-nmethyldaspartate-receptor-type-1-partial-agonism-1", "reader_count"=>2, "reader_count_by_academic_status"=>{"Student > Doctoral Student"=>1, "Student > Bachelor"=>1}, "reader_count_by_user_role"=>{"Student > Doctoral Student"=>1, "Student > Bachelor"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>1, "Agricultural and Biological Sciences"=>1}, "reader_count_by_subdiscipline"=>{"Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/297275", "https://ndownloader.figshare.com/files/297316", "https://ndownloader.figshare.com/files/297403", "https://ndownloader.figshare.com/files/297442"], "description"=>"<div><p><em>N</em>-methyl-D-aspartate (NMDA) receptors belong to a family of ionotropic glutamate receptors that contribute to the signal transmission in the central nervous system. NMDA receptors are heterotetramers that usually consist of two GluN1 and GluN2 monomers. The extracellular ligand-binding domain (LBD) of a monomer is comprised of discontinuous segments that form the functional domains D1 and D2. While the binding of a full agonist glycine to LBD of GluN1 is linked to cleft closure and subsequent ion-channel opening, partial agonists are known to activate the receptor only sub-maximally. Although the crystal structures of the LBD of related GluA2 receptor explain the mechanism for the partial agonism, structures of GluN1-LBD cannot distinguish the difference between full and partial agonists. It is, however, probable that the partial agonists of GluN1 alter the structure of the LBD in order to result in a different pharmacological response than seen with full agonists. In this study, we used molecular dynamics simulations to reveal an intermediate closure-stage for GluN1, which is unseen in crystal structures. According to our calculations, this intermediate closure is not a transient stage but an energetically stable conformation. Our results demonstrate that the partial agonist cannot exert firm GluN1-LBD closure, especially if there is even a small force that disrupts the LBD closure. Accordingly, this result suggests the importance of forces from the ion channel for the relationship between pharmacological response and the structure of the LBD of members of this receptor family.</p> </div>", "links"=>[], "tags"=>["receptor", "agonism"], "article_id"=>118592, "categories"=>["Biological Sciences", "Biochemistry", "Neuroscience", "Biophysics"], "users"=>["Mikko Ylilauri", "Olli T. Pentikäinen"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0047604.s001", "https://dx.doi.org/10.1371/journal.pone.0047604.s002", "https://dx.doi.org/10.1371/journal.pone.0047604.s003", "https://dx.doi.org/10.1371/journal.pone.0047604.s004"], "stats"=>{"downloads"=>7, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Structural_Mechanism_of_N_Methyl_D_Aspartate_Receptor_Type_1_Partial_Agonism/118592", "title"=>"Structural Mechanism of <em>N</em>-Methyl-D-Aspartate Receptor Type 1 Partial Agonism", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-10-15 02:23:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/558877"], "description"=>"<p>Free MD simulations starting from (A) open and (B) closed LBD, and (C) SMD simulations (9 pN) from a closed LBD. The distances (left panel) are IHB distances (Gly485<sup>N</sup>-Gln686<sup>O</sup>). Corresponding binding enthalpies (ΔH) from the simulations are shown in the right panel. Results from all the SMD simulations performed are shown in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047604#pone.0047604.s001\" target=\"_blank\">Figure S2</a>.</p>", "links"=>[], "tags"=>["glun1-lbd", "closure", "ligand"], "article_id"=>229374, "categories"=>["Biological Sciences", "Biochemistry", "Neuroscience", "Biophysics"], "users"=>["Mikko Ylilauri", "Olli T. Pentikäinen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0047604.g003", "stats"=>{"downloads"=>2, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Relationship_of_GluN1_LBD_closure_and_916_H_in_ligand_binding_/229374", "title"=>"Relationship of GluN1-LBD closure and ΔH in ligand binding.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-15 02:36:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/559037"], "description"=>"<p>(A) Model showing the hypothesized conformational changes taking place at LBD and TM domain in binding of either an agonist or antagonist to cleft between D1 and D2. Agonist and antagonist bound models are colored green and red, respectively. Colored arrows depict the hypothesized forces affecting the conformation of the domains (full agonist in green, partial agonist in yellow and antagonist in red). (B) Distance measurements of Gly458<sup>N</sup>-Gln686<sup>O</sup> and Gln405<sup>OE1</sup>-Trp731<sup>NE1</sup> from D-cycloserine bound open-cleft GluN1-LBD taken from a constraint-free MD simulation trajectory. Comparison of the two distances reveals that there is a difference in the swiftness of closure of the LBD at various sides of the binding cleft. In addition, the intermediate closure is not seen ubiquitously at the binding cavity. In (C), superimposed structures are taken from the trajectory of the simulation in (B). The starting structure, cycloleucine-bound open-cleft GluN1 (PDB: 1Y1M), is colored red. Snapshots from intermediately closed (yellow) and fully closed (green) LBD are taken at time steps of 13 and 19 ns, respectively. In (D), part of an iGluR monomer (from GluA2 structure, PDB: 3KG2) show that the IHB is directly linked to M3. The purple ball represents the location of Gly458, which is the IHB-residue at D2 side of GluN1-LBD. Locations of Trp731 and Ala715 are depicted as orange and pink balls, respectively.</p>", "links"=>[], "tags"=>["glun1-lbd", "transmembrane"], "article_id"=>229534, "categories"=>["Biological Sciences", "Biochemistry", "Neuroscience", "Biophysics"], "users"=>["Mikko Ylilauri", "Olli T. Pentikäinen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0047604.g004", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Closure_mechanism_of_GluN1_LBD_and_connection_to_transmembrane_domain_/229534", "title"=>"Closure mechanism of GluN1-LBD and connection to transmembrane domain.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-15 02:38:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/559131"], "description"=>"a<p>Calculated as average distances between Gly485<sup>N</sup> and Gln686<sup>O</sup> at the intermediate closure stage. For glycine, distance is measured from PDB-structure 1PB7.</p>b<p>Experimental efficacies (from GluN1/GluN2B assemblies) compared to glycine. Data for D-cycloserine and ACBC from <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047604#pone.0047604-Priestley2\" target=\"_blank\">[40]</a>, ACPC from <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047604#pone.0047604-Inanobe1\" target=\"_blank\">[12]</a>.</p>c<p>Average ΔH calculated by MMGB/SA from the time-span of intermediate closure. For glycine, ΔH was averaged from the time period of fully closed state.</p>d<p>EC<sub>50</sub> data (from GluN1/GluN2B assemblies) obtained from literature: glycine and ACPC from <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047604#pone.0047604-Chen1\" target=\"_blank\">[19]</a>, D-cycloserine and ACBC from <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047604#pone.0047604-Dravid1\" target=\"_blank\">[35]</a> and <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047604#pone.0047604-Priestley2\" target=\"_blank\">[40]</a>, respectively.</p>", "links"=>[], "tags"=>["ihb", "smd", "simulations", "compared", "experimentally", "efficacies", "glun1"], "article_id"=>229616, "categories"=>["Biological Sciences", "Biochemistry", "Neuroscience", "Biophysics"], "users"=>["Mikko Ylilauri", "Olli T. Pentikäinen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0047604.t001", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Average_IHB_distance_and_H_from_SMD_simulations_compared_to_experimentally_obtained_efficacies_and_EC_50_values_for_various_GluN1_agonists_/229616", "title"=>"Average IHB distance and ΔH from SMD simulations compared to experimentally obtained efficacies and EC<sub>50</sub> values for various GluN1 agonists.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-10-15 02:40:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/558548"], "description"=>"<p>(A) The crystal structure of GluA2 shows that it functions as a tetramer and (B) that the closure of the LBD determines the pharmacological behavior of GluA2. (C) On the contrary to GluA2, partial agonism of the NMDA receptors is ambiguous. In (A), one LBD (from PDB: 3KG2) is highlighted in red. The arrows depict the potential forces that occur during full agonist binding (green), partial agonist binding (yellow), and closure of the ion channel (red). In (B) and (C), superimposed structures with full agonist (green), partial agonist (yellow), and antagonist (red) are shown. Ligand binding site between domains D1 and D2 is depicted as letter L. Structures (PDB-codes) used are 3KG2 <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047604#pone.0047604-Sobolevsky1\" target=\"_blank\">[7]</a> in (A), 1FTJ, 1FTK, and 1FTL <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047604#pone.0047604-Armstrong2\" target=\"_blank\">[13]</a> in (B) and 1PB7, 1PB9, and 1Y1M <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047604#pone.0047604-Furukawa1\" target=\"_blank\">[11]</a>, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047604#pone.0047604-Inanobe1\" target=\"_blank\">[12]</a> in (C).</p>", "links"=>[], "tags"=>["Computational biology", "biophysics", "neuroscience", "Biochemistry"], "article_id"=>229047, "categories"=>["Biological Sciences", "Biochemistry", "Neuroscience", "Biophysics"], "users"=>["Mikko Ylilauri", "Olli T. Pentikäinen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0047604.g001", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_crystal_structure_of_iGluRs_/229047", "title"=>"The crystal structure of iGluRs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-15 02:30:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/558706"], "description"=>"<p>Free MD simulations indicate that (A) D-cycloserine and (B) glycine bound to open-cleft GluN1 (from PDB: 1Y1M) can close the LBD between D1 and D2, as seen in the crystal structures. (C) Contrary to crystal structures, a stable intermediate closure stage is seen in GluN1-LBD with bound partial agonists. Superimposition of a snapshot from a D-cycloserine simulation in Fig. 3A (blue line) with crystal structures of the same ligand (PDB: 1PB9) and antagonist ligand cycloleucine (from PDB: 1Y1M) is shown. Cα atoms of IHB residues (Gly485 and Gln686), as well as of residues Gln405 and Ala715, are depicted as CPK, and dotted lines represent the distances measured to study the closure of the cleft. (D) A close-up of the intermediately closed GluN1-D-cycloserine structures in free MD simulations – starting from both closed and open-cleft structures – as well as in SMD simulation starting from a closed-cleft structure (6 pN, blue line in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047604#pone.0047604.s002\" target=\"_blank\">Figure S2</a>). Crystal structures of GluN1 with bound D-cycloserine (from PDB: 1PB9) and cycloleucine (from PDB: 1Y1M) are superimposed for comparison. Dotted lines in (A), (B), and (D) represent the IHB distance between Gly485<sup>N</sup> and Gln686<sup>O</sup>, which is an efficient indicator of cleft closure.</p>", "links"=>[], "tags"=>["smd", "simulations", "ligand-bound"], "article_id"=>229202, "categories"=>["Biological Sciences", "Biochemistry", "Neuroscience", "Biophysics"], "users"=>["Mikko Ylilauri", "Olli T. Pentikäinen"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0047604.g002", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MD_and_SMD_simulations_of_ligand_bound_GluN1_LBD_/229202", "title"=>"MD and SMD simulations of ligand-bound GluN1-LBD.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-15 02:33:22"}

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Relative Metric

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