Tsung-Han Chou, Max Epstein, Russell G. Fritzemeier, Nicholas S. Akins, Srinu Paladugu, Elijah Z. Ullman, Dennis C. Liotta, Stephen F. Traynelis, Hiro Furukawa
{"title":"配体门控和 NMDA 受体开放的分子机制。","authors":"Tsung-Han Chou, Max Epstein, Russell G. Fritzemeier, Nicholas S. Akins, Srinu Paladugu, Elijah Z. Ullman, Dennis C. Liotta, Stephen F. Traynelis, Hiro Furukawa","doi":"10.1038/s41586-024-07742-0","DOIUrl":null,"url":null,"abstract":"Glutamate transmission and activation of ionotropic glutamate receptors are the fundamental means by which neurons control their excitability and neuroplasticity1. The N-methyl-d-aspartate receptor (NMDAR) is unique among all ligand-gated channels, requiring two ligands—glutamate and glycine—for activation. These receptors function as heterotetrameric ion channels, with the channel opening dependent on the simultaneous binding of glycine and glutamate to the extracellular ligand-binding domains (LBDs) of the GluN1 and GluN2 subunits, respectively2,3. The exact molecular mechanism for channel gating by the two ligands has been unclear, particularly without structures representing the open channel and apo states. Here we show that the channel gate opening requires tension in the linker connecting the LBD and transmembrane domain (TMD) and rotation of the extracellular domain relative to the TMD. Using electron cryomicroscopy, we captured the structure of the GluN1–GluN2B (GluN1–2B) NMDAR in its open state bound to a positive allosteric modulator. This process rotates and bends the pore-forming helices in GluN1 and GluN2B, altering the symmetry of the TMD channel from pseudofourfold to twofold. Structures of GluN1–2B NMDAR in apo and single-liganded states showed that binding of either glycine or glutamate alone leads to distinct GluN1–2B dimer arrangements but insufficient tension in the LBD–TMD linker for channel opening. This mechanistic framework identifies a key determinant for channel gating and a potential pharmacological strategy for modulating NMDAR activity. Cryo-electron microscopy structures of NMDA receptors in open and apo states reveal the molecular mechanism underlying the dual ligand requirement for its channel gating and opening.","PeriodicalId":18787,"journal":{"name":"Nature","volume":null,"pages":null},"PeriodicalIF":50.5000,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Molecular mechanism of ligand gating and opening of NMDA receptor\",\"authors\":\"Tsung-Han Chou, Max Epstein, Russell G. Fritzemeier, Nicholas S. Akins, Srinu Paladugu, Elijah Z. Ullman, Dennis C. Liotta, Stephen F. Traynelis, Hiro Furukawa\",\"doi\":\"10.1038/s41586-024-07742-0\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Glutamate transmission and activation of ionotropic glutamate receptors are the fundamental means by which neurons control their excitability and neuroplasticity1. The N-methyl-d-aspartate receptor (NMDAR) is unique among all ligand-gated channels, requiring two ligands—glutamate and glycine—for activation. These receptors function as heterotetrameric ion channels, with the channel opening dependent on the simultaneous binding of glycine and glutamate to the extracellular ligand-binding domains (LBDs) of the GluN1 and GluN2 subunits, respectively2,3. The exact molecular mechanism for channel gating by the two ligands has been unclear, particularly without structures representing the open channel and apo states. Here we show that the channel gate opening requires tension in the linker connecting the LBD and transmembrane domain (TMD) and rotation of the extracellular domain relative to the TMD. Using electron cryomicroscopy, we captured the structure of the GluN1–GluN2B (GluN1–2B) NMDAR in its open state bound to a positive allosteric modulator. This process rotates and bends the pore-forming helices in GluN1 and GluN2B, altering the symmetry of the TMD channel from pseudofourfold to twofold. Structures of GluN1–2B NMDAR in apo and single-liganded states showed that binding of either glycine or glutamate alone leads to distinct GluN1–2B dimer arrangements but insufficient tension in the LBD–TMD linker for channel opening. This mechanistic framework identifies a key determinant for channel gating and a potential pharmacological strategy for modulating NMDAR activity. Cryo-electron microscopy structures of NMDA receptors in open and apo states reveal the molecular mechanism underlying the dual ligand requirement for its channel gating and opening.\",\"PeriodicalId\":18787,\"journal\":{\"name\":\"Nature\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":50.5000,\"publicationDate\":\"2024-07-31\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature\",\"FirstCategoryId\":\"103\",\"ListUrlMain\":\"https://www.nature.com/articles/s41586-024-07742-0\",\"RegionNum\":1,\"RegionCategory\":\"综合性期刊\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MULTIDISCIPLINARY SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature","FirstCategoryId":"103","ListUrlMain":"https://www.nature.com/articles/s41586-024-07742-0","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
Molecular mechanism of ligand gating and opening of NMDA receptor
Glutamate transmission and activation of ionotropic glutamate receptors are the fundamental means by which neurons control their excitability and neuroplasticity1. The N-methyl-d-aspartate receptor (NMDAR) is unique among all ligand-gated channels, requiring two ligands—glutamate and glycine—for activation. These receptors function as heterotetrameric ion channels, with the channel opening dependent on the simultaneous binding of glycine and glutamate to the extracellular ligand-binding domains (LBDs) of the GluN1 and GluN2 subunits, respectively2,3. The exact molecular mechanism for channel gating by the two ligands has been unclear, particularly without structures representing the open channel and apo states. Here we show that the channel gate opening requires tension in the linker connecting the LBD and transmembrane domain (TMD) and rotation of the extracellular domain relative to the TMD. Using electron cryomicroscopy, we captured the structure of the GluN1–GluN2B (GluN1–2B) NMDAR in its open state bound to a positive allosteric modulator. This process rotates and bends the pore-forming helices in GluN1 and GluN2B, altering the symmetry of the TMD channel from pseudofourfold to twofold. Structures of GluN1–2B NMDAR in apo and single-liganded states showed that binding of either glycine or glutamate alone leads to distinct GluN1–2B dimer arrangements but insufficient tension in the LBD–TMD linker for channel opening. This mechanistic framework identifies a key determinant for channel gating and a potential pharmacological strategy for modulating NMDAR activity. Cryo-electron microscopy structures of NMDA receptors in open and apo states reveal the molecular mechanism underlying the dual ligand requirement for its channel gating and opening.
期刊介绍:
Nature is a prestigious international journal that publishes peer-reviewed research in various scientific and technological fields. The selection of articles is based on criteria such as originality, importance, interdisciplinary relevance, timeliness, accessibility, elegance, and surprising conclusions. In addition to showcasing significant scientific advances, Nature delivers rapid, authoritative, insightful news, and interpretation of current and upcoming trends impacting science, scientists, and the broader public. The journal serves a dual purpose: firstly, to promptly share noteworthy scientific advances and foster discussions among scientists, and secondly, to ensure the swift dissemination of scientific results globally, emphasizing their significance for knowledge, culture, and daily life.