Probing the Structural Dynamics of the NMDA Receptor Activation by Coarse-Grained Modeling
N-Methyl-D-aspartate (NMDA) receptors are glutamate-gated excitatory channels that play essential roles in brain functions. High-resolution structures have been solved for an allosterically inhibited and agonist-bound form of a functional NMDA receptor; however, other key functional states (particul...
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description | N-Methyl-D-aspartate (NMDA) receptors are glutamate-gated excitatory channels that play essential roles in brain functions. High-resolution structures have been solved for an allosterically inhibited and agonist-bound form of a functional NMDA receptor; however, other key functional states (particularly the active open-channel state) were only resolved at moderate resolutions by cryo-electron microscopy (cryo-EM). To decrypt the mechanism of the NMDA receptor activation, structural modeling is essential to provide presently missing information about structural dynamics. We performed systematic coarse-grained modeling using an elastic network model and related modeling/analysis tools (e.g., normal mode analysis, flexibility and hotspot analysis, cryo-EM flexible fitting, and transition pathway modeling) based on an active-state cryo-EM map. We observed extensive conformational changes that allosterically couple the extracellular regulatory and agonist-binding domains to the pore-forming trans-membrane domain (TMD), and validated these, to our knowledge, new observations against known mutational and functional studies. Our results predict two key modes of collective motions featuring shearing/twisting of the extracellular domains relative to the TMD, reveal subunit-specific flexibility profiles, and identify functional hotspot residues at key domain-domain interfaces. Finally, by examining the conformational transition pathway between the allosterically inhibited form and the active form, we predict a discrete sequence of domain motions, which propagate from the extracellular domains to the TMD. In summary, our results offer rich structural and dynamic information, which is consistent with the literature on structure-function relationships in NMDA receptors, and will guide in-depth studies on the activation dynamics of this important neurotransmitter receptor. |
doi_str_mv | 10.1016/j.bpj.2017.04.043 |
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High-resolution structures have been solved for an allosterically inhibited and agonist-bound form of a functional NMDA receptor; however, other key functional states (particularly the active open-channel state) were only resolved at moderate resolutions by cryo-electron microscopy (cryo-EM). To decrypt the mechanism of the NMDA receptor activation, structural modeling is essential to provide presently missing information about structural dynamics. We performed systematic coarse-grained modeling using an elastic network model and related modeling/analysis tools (e.g., normal mode analysis, flexibility and hotspot analysis, cryo-EM flexible fitting, and transition pathway modeling) based on an active-state cryo-EM map. We observed extensive conformational changes that allosterically couple the extracellular regulatory and agonist-binding domains to the pore-forming trans-membrane domain (TMD), and validated these, to our knowledge, new observations against known mutational and functional studies. Our results predict two key modes of collective motions featuring shearing/twisting of the extracellular domains relative to the TMD, reveal subunit-specific flexibility profiles, and identify functional hotspot residues at key domain-domain interfaces. Finally, by examining the conformational transition pathway between the allosterically inhibited form and the active form, we predict a discrete sequence of domain motions, which propagate from the extracellular domains to the TMD. In summary, our results offer rich structural and dynamic information, which is consistent with the literature on structure-function relationships in NMDA receptors, and will guide in-depth studies on the activation dynamics of this important neurotransmitter receptor.</description><identifier>ISSN: 0006-3495</identifier><identifier>EISSN: 1542-0086</identifier><identifier>DOI: 10.1016/j.bpj.2017.04.043</identifier><identifier>PMID: 28636915</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Activation ; Activation analysis ; Allosteric Regulation ; Analysis ; Animals ; Brain ; Cryoelectron Microscopy ; Dynamic structural analysis ; Elasticity ; Electron microscopy ; Flexibility ; Glutamic acid receptors (ionotropic) ; High resolution ; Interfaces ; Mathematical models ; Modelling ; Models, Molecular ; Mutation ; N-Methyl-D-aspartic acid receptors ; Pore formation ; Protein Conformation ; Proteins ; Rats ; Receptor mechanisms ; Receptors ; Receptors, N-Methyl-D-Aspartate - agonists ; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors ; Receptors, N-Methyl-D-Aspartate - genetics ; Receptors, N-Methyl-D-Aspartate - metabolism ; Shearing ; Structure-function relationships ; Transmission electron microscopy ; Twisting ; Xenopus laevis</subject><ispartof>Biophysical journal, 2017-06, Vol.112 (12), p.2589-2601</ispartof><rights>2017 Biophysical Society</rights><rights>Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.</rights><rights>Copyright Biophysical Society Jun 20, 2017</rights><rights>2017 Biophysical Society. 2017 Biophysical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c479t-3811d68b75e2ba11b82e6fc04f72e3661a126c866013c357c8a6b694153637263</citedby><cites>FETCH-LOGICAL-c479t-3811d68b75e2ba11b82e6fc04f72e3661a126c866013c357c8a6b694153637263</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479051/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bpj.2017.04.043$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,3550,27924,27925,45995,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28636915$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zheng, Wenjun</creatorcontrib><creatorcontrib>Wen, Han</creatorcontrib><creatorcontrib>Iacobucci, Gary J.</creatorcontrib><creatorcontrib>Popescu, Gabriela K.</creatorcontrib><title>Probing the Structural Dynamics of the NMDA Receptor Activation by Coarse-Grained Modeling</title><title>Biophysical journal</title><addtitle>Biophys J</addtitle><description>N-Methyl-D-aspartate (NMDA) receptors are glutamate-gated excitatory channels that play essential roles in brain functions. High-resolution structures have been solved for an allosterically inhibited and agonist-bound form of a functional NMDA receptor; however, other key functional states (particularly the active open-channel state) were only resolved at moderate resolutions by cryo-electron microscopy (cryo-EM). To decrypt the mechanism of the NMDA receptor activation, structural modeling is essential to provide presently missing information about structural dynamics. We performed systematic coarse-grained modeling using an elastic network model and related modeling/analysis tools (e.g., normal mode analysis, flexibility and hotspot analysis, cryo-EM flexible fitting, and transition pathway modeling) based on an active-state cryo-EM map. We observed extensive conformational changes that allosterically couple the extracellular regulatory and agonist-binding domains to the pore-forming trans-membrane domain (TMD), and validated these, to our knowledge, new observations against known mutational and functional studies. Our results predict two key modes of collective motions featuring shearing/twisting of the extracellular domains relative to the TMD, reveal subunit-specific flexibility profiles, and identify functional hotspot residues at key domain-domain interfaces. Finally, by examining the conformational transition pathway between the allosterically inhibited form and the active form, we predict a discrete sequence of domain motions, which propagate from the extracellular domains to the TMD. In summary, our results offer rich structural and dynamic information, which is consistent with the literature on structure-function relationships in NMDA receptors, and will guide in-depth studies on the activation dynamics of this important neurotransmitter receptor.</description><subject>Activation</subject><subject>Activation analysis</subject><subject>Allosteric Regulation</subject><subject>Analysis</subject><subject>Animals</subject><subject>Brain</subject><subject>Cryoelectron Microscopy</subject><subject>Dynamic structural analysis</subject><subject>Elasticity</subject><subject>Electron microscopy</subject><subject>Flexibility</subject><subject>Glutamic acid receptors (ionotropic)</subject><subject>High resolution</subject><subject>Interfaces</subject><subject>Mathematical models</subject><subject>Modelling</subject><subject>Models, Molecular</subject><subject>Mutation</subject><subject>N-Methyl-D-aspartic acid receptors</subject><subject>Pore formation</subject><subject>Protein Conformation</subject><subject>Proteins</subject><subject>Rats</subject><subject>Receptor mechanisms</subject><subject>Receptors</subject><subject>Receptors, N-Methyl-D-Aspartate - agonists</subject><subject>Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors</subject><subject>Receptors, N-Methyl-D-Aspartate - genetics</subject><subject>Receptors, N-Methyl-D-Aspartate - metabolism</subject><subject>Shearing</subject><subject>Structure-function relationships</subject><subject>Transmission electron microscopy</subject><subject>Twisting</subject><subject>Xenopus laevis</subject><issn>0006-3495</issn><issn>1542-0086</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU9v1DAQxSMEokvhA3BBkbhwyTJjx04iJKTVlhakFhB_Llwsx5m0jrLxYjsr7bevly0VcEAayYf5zfO8eVn2HGGJgPL1sGy3w5IBVksoU_EH2QJFyQqAWj7MFgAgC1424iR7EsIAgEwAPs5OWC25bFAssh-fvWvtdJ3HG8q_Rj-bOHs95mf7SW-sCbnrf7U-Xp2t8i9kaBudz1cm2p2O1k15u8_XTvtAxYXXdqIuv3IdjUnyafao12OgZ3fvafb9_N239fvi8tPFh_XqsjBl1cSC14idrNtKEGs1Ylszkr2Bsq8YcSlRI5OmlhKQGy4qU2vZyqZEwSWvmOSn2duj7nZuN9QZmmJyoLbebrTfK6et-rsz2Rt17XZKpP9BYBJ4dSfg3c-ZQlQbGwyNo57IzUFhkzaAWrAD-vIfdHCzn5K9RDEOpQAmEoVHyngXgqf-fhkEdUhODSolpw7JKShT8TTz4k8X9xO_o0rAmyNA6ZY7S14FY2ky1FlPJqrO2f_I3wJNlKfM</recordid><startdate>20170620</startdate><enddate>20170620</enddate><creator>Zheng, Wenjun</creator><creator>Wen, Han</creator><creator>Iacobucci, Gary J.</creator><creator>Popescu, Gabriela K.</creator><general>Elsevier Inc</general><general>Biophysical Society</general><general>The Biophysical Society</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7QP</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170620</creationdate><title>Probing the Structural Dynamics of the NMDA Receptor Activation by Coarse-Grained Modeling</title><author>Zheng, Wenjun ; Wen, Han ; Iacobucci, Gary J. ; Popescu, Gabriela K.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c479t-3811d68b75e2ba11b82e6fc04f72e3661a126c866013c357c8a6b694153637263</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Activation</topic><topic>Activation analysis</topic><topic>Allosteric Regulation</topic><topic>Analysis</topic><topic>Animals</topic><topic>Brain</topic><topic>Cryoelectron Microscopy</topic><topic>Dynamic structural analysis</topic><topic>Elasticity</topic><topic>Electron microscopy</topic><topic>Flexibility</topic><topic>Glutamic acid receptors (ionotropic)</topic><topic>High resolution</topic><topic>Interfaces</topic><topic>Mathematical models</topic><topic>Modelling</topic><topic>Models, Molecular</topic><topic>Mutation</topic><topic>N-Methyl-D-aspartic acid receptors</topic><topic>Pore formation</topic><topic>Protein Conformation</topic><topic>Proteins</topic><topic>Rats</topic><topic>Receptor mechanisms</topic><topic>Receptors</topic><topic>Receptors, N-Methyl-D-Aspartate - agonists</topic><topic>Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors</topic><topic>Receptors, N-Methyl-D-Aspartate - genetics</topic><topic>Receptors, N-Methyl-D-Aspartate - metabolism</topic><topic>Shearing</topic><topic>Structure-function relationships</topic><topic>Transmission electron microscopy</topic><topic>Twisting</topic><topic>Xenopus laevis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zheng, Wenjun</creatorcontrib><creatorcontrib>Wen, Han</creatorcontrib><creatorcontrib>Iacobucci, Gary J.</creatorcontrib><creatorcontrib>Popescu, Gabriela K.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Biophysical journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zheng, Wenjun</au><au>Wen, Han</au><au>Iacobucci, Gary J.</au><au>Popescu, Gabriela K.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Probing the Structural Dynamics of the NMDA Receptor Activation by Coarse-Grained Modeling</atitle><jtitle>Biophysical journal</jtitle><addtitle>Biophys J</addtitle><date>2017-06-20</date><risdate>2017</risdate><volume>112</volume><issue>12</issue><spage>2589</spage><epage>2601</epage><pages>2589-2601</pages><issn>0006-3495</issn><eissn>1542-0086</eissn><abstract>N-Methyl-D-aspartate (NMDA) receptors are glutamate-gated excitatory channels that play essential roles in brain functions. High-resolution structures have been solved for an allosterically inhibited and agonist-bound form of a functional NMDA receptor; however, other key functional states (particularly the active open-channel state) were only resolved at moderate resolutions by cryo-electron microscopy (cryo-EM). To decrypt the mechanism of the NMDA receptor activation, structural modeling is essential to provide presently missing information about structural dynamics. We performed systematic coarse-grained modeling using an elastic network model and related modeling/analysis tools (e.g., normal mode analysis, flexibility and hotspot analysis, cryo-EM flexible fitting, and transition pathway modeling) based on an active-state cryo-EM map. We observed extensive conformational changes that allosterically couple the extracellular regulatory and agonist-binding domains to the pore-forming trans-membrane domain (TMD), and validated these, to our knowledge, new observations against known mutational and functional studies. Our results predict two key modes of collective motions featuring shearing/twisting of the extracellular domains relative to the TMD, reveal subunit-specific flexibility profiles, and identify functional hotspot residues at key domain-domain interfaces. Finally, by examining the conformational transition pathway between the allosterically inhibited form and the active form, we predict a discrete sequence of domain motions, which propagate from the extracellular domains to the TMD. In summary, our results offer rich structural and dynamic information, which is consistent with the literature on structure-function relationships in NMDA receptors, and will guide in-depth studies on the activation dynamics of this important neurotransmitter receptor.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>28636915</pmid><doi>10.1016/j.bpj.2017.04.043</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Activation Activation analysis Allosteric Regulation Analysis Animals Brain Cryoelectron Microscopy Dynamic structural analysis Elasticity Electron microscopy Flexibility Glutamic acid receptors (ionotropic) High resolution Interfaces Mathematical models Modelling Models, Molecular Mutation N-Methyl-D-aspartic acid receptors Pore formation Protein Conformation Proteins Rats Receptor mechanisms Receptors Receptors, N-Methyl-D-Aspartate - agonists Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors Receptors, N-Methyl-D-Aspartate - genetics Receptors, N-Methyl-D-Aspartate - metabolism Shearing Structure-function relationships Transmission electron microscopy Twisting Xenopus laevis |
title | Probing the Structural Dynamics of the NMDA Receptor Activation by Coarse-Grained Modeling |
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