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  • 1
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    Subunit arrangement and phenylethanolamine binding in GluN1/GluN2B NMDA receptors (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-06-17
    Description: Since it was discovered that the anti-hypertensive agent ifenprodil has neuroprotective activity through its effects on NMDA (N-methyl-D-aspartate) receptors, a determined effort has been made to understand the mechanism of action and to develop improved therapeutic compounds on the basis of this knowledge. Neurotransmission mediated by NMDA receptors is essential for basic brain development and function. These receptors form heteromeric ion channels and become activated after concurrent binding of glycine and glutamate to the GluN1 and GluN2 subunits, respectively. A functional hallmark of NMDA receptors is that their ion-channel activity is allosterically regulated by binding of small compounds to the amino-terminal domain (ATD) in a subtype-specific manner. Ifenprodil and related phenylethanolamine compounds, which specifically inhibit GluN1 and GluN2B NMDA receptors, have been intensely studied for their potential use in the treatment of various neurological disorders and diseases, including depression, Alzheimer's disease and Parkinson's disease. Despite considerable enthusiasm, mechanisms underlying the recognition of phenylethanolamines and ATD-mediated allosteric inhibition remain limited owing to a lack of structural information. Here we report that the GluN1 and GluN2B ATDs form a heterodimer and that phenylethanolamine binds at the interface between GluN1 and GluN2B, rather than within the GluN2B cleft. The crystal structure of the heterodimer formed between the GluN1b ATD from Xenopus laevis and the GluN2B ATD from Rattus norvegicus shows a highly distinct pattern of subunit arrangement that is different from the arrangements observed in homodimeric non-NMDA receptors and reveals the molecular determinants for phenylethanolamine binding. Restriction of domain movement in the bi-lobed structure of the GluN2B ATD, by engineering of an inter-subunit disulphide bond, markedly decreases sensitivity to ifenprodil, indicating that conformational freedom in the GluN2B ATD is essential for ifenprodil-mediated allosteric inhibition of NMDA receptors. These findings pave the way for improving the design of subtype-specific compounds with therapeutic value for neurological disorders and diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3171209/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3171209/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Karakas, Erkan -- Simorowski, Noriko -- Furukawa, Hiro -- MH085926/MH/NIMH NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 MH085926/MH/NIMH NIH HHS/ -- R01 MH085926-01A1/MH/NIMH NIH HHS/ -- R01 MH085926-02/MH/NIMH NIH HHS/ -- R01 MH085926-03/MH/NIMH NIH HHS/ -- England -- Nature. 2011 Jun 15;475(7355):249-53. doi: 10.1038/nature10180.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cold Spring Harbor Laboratory, WM Keck Structural Biology Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21677647" target="_blank"〉PubMed〈/a〉
    Keywords: 2-Hydroxyphenethylamine/chemistry/*metabolism/pharmacology ; Allosteric Regulation/drug effects ; Animals ; Binding Sites ; Crystallography, X-Ray ; Disulfides/chemistry/metabolism ; Movement ; Neuroprotective Agents/pharmacology ; Piperidines/chemistry/*metabolism/pharmacology ; Protein Multimerization ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; Rats ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/*chemistry/*metabolism ; Xenopus laevis
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Crystal structure of a heterotetrameric NMDA receptor ion channel (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-05-31
    Description: N-Methyl-D-aspartate (NMDA) receptors belong to the family of ionotropic glutamate receptors, which mediate most excitatory synaptic transmission in mammalian brains. Calcium permeation triggered by activation of NMDA receptors is the pivotal event for initiation of neuronal plasticity. Here, we show the crystal structure of the intact heterotetrameric GluN1-GluN2B NMDA receptor ion channel at 4 angstroms. The NMDA receptors are arranged as a dimer of GluN1-GluN2B heterodimers with the twofold symmetry axis running through the entire molecule composed of an amino terminal domain (ATD), a ligand-binding domain (LBD), and a transmembrane domain (TMD). The ATD and LBD are much more highly packed in the NMDA receptors than non-NMDA receptors, which may explain why ATD regulates ion channel activity in NMDA receptors but not in non-NMDA receptors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113085/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113085/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Karakas, Erkan -- Furukawa, Hiro -- MH085926/MH/NIMH NIH HHS/ -- R01 GM105730/GM/NIGMS NIH HHS/ -- R01 MH085926/MH/NIMH NIH HHS/ -- New York, N.Y. -- Science. 2014 May 30;344(6187):992-7. doi: 10.1126/science.1251915.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cold Spring Harbor Laboratory, W. M. Keck Structural Biology Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724, USA. ; Cold Spring Harbor Laboratory, W. M. Keck Structural Biology Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724, USA. furukawa@cshl.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24876489" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Calcium/chemistry/metabolism ; Crystallography, X-Ray ; Protein Multimerization ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Rats ; Receptors, N-Methyl-D-Aspartate/*chemistry/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 3
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    Activation of NMDA receptors and the mechanism of inhibition by ifenprodil (2016)
    Nature Publishing Group (NPG)
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    Publication Date: 2016-05-03
    Description: The physiology of N-methyl-d-aspartate (NMDA) receptors is fundamental to brain development and function. NMDA receptors are ionotropic glutamate receptors that function as heterotetramers composed mainly of GluN1 and GluN2 subunits. Activation of NMDA receptors requires binding of neurotransmitter agonists to a ligand-binding domain (LBD) and structural rearrangement of an amino-terminal domain (ATD). Recent crystal structures of GluN1-GluN2B NMDA receptors bound to agonists and an allosteric inhibitor, ifenprodil, represent the allosterically inhibited state. However, how the ATD and LBD move to activate the NMDA receptor ion channel remains unclear. Here we applied X-ray crystallography, single-particle electron cryomicroscopy and electrophysiology to rat NMDA receptors to show that, in the absence of ifenprodil, the bi-lobed structure of GluN2 ATD adopts an open conformation accompanied by rearrangement of the GluN1-GluN2 ATD heterodimeric interface, altering subunit orientation in the ATD and LBD and forming an active receptor conformation that gates the ion channel.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tajima, Nami -- Karakas, Erkan -- Grant, Timothy -- Simorowski, Noriko -- Diaz-Avalos, Ruben -- Grigorieff, Nikolaus -- Furukawa, Hiro -- Nature. 2016 May 2. doi: 10.1038/nature17679.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cold Spring Harbor Laboratory, W. M. Keck Structural Biology Laboratory, Cold Spring Harbor, New York 11724, USA. ; Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia 20147, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27135925" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 4
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    Post‐earthquake aggradation processes to hide surface ruptures in thrust systems: The M8.3, 1934, Bihar‐Nepal earthquake ruptures at Charnath Khola (Eastern Nepal) (2019)
    Wiley
    Details
    Publication Date: 2019
    Description: Abstract The Charnath Khola is a large river crossing the Himalayan thrust system in the region devastated by the great M 8.3 1934 Bihar‐Nepal earthquake. Fluvial terraces are abandoned along the river and at the base of a ~20 m‐high cumulative thrust escarpment. A trench across the fault scarp exposed Siwalik mudstone/siltstone overthrusting Quaternary units and three colluvial wedges interfingered with fluvial sands. 85 AMS radiocarbon dates, from detrital charcoals sampled in the trench, a rivercut and river terraces, constrain the timing of the sedimentary processes following the last two major earthquakes, in 1934 and 1255 CE. Although several samples straddle the main earthquake horizon, associating it with the 1934 earthquake, based solely on radiocarbon ages, remains challenging. The 49 detrital charcoal ages found in the pre‐ and post‐earthquake units fall between 65 BP and 225 BP, a period with a flat calibration curve. Many of these radiocarbon ages are suspected to include a part due to inbuilt time (i.e., age of the wood at the time of burning), transport time, and reworking processes, which are difficult to resolve. Considering these ages at their face value could lead to dates older than the actual earthquake dates. We suggest that a part of this chronological bias is also related to a local post‐seismic aggradation pulse of 4 to 5 metres of sediments, which is documented in the trench and terraces. This fluvial sequence, hiding the most recent surface rupture, is likely related to landslide‐sediment deposition triggered by the 1934 Bihar‐Nepal earthquake.
    Print ISSN: 2169-9313
    Electronic ISSN: 2169-9356
    Topics: Geosciences , Physics
    Published by Wiley on behalf of American Geophysical Union (AGU).
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  • 5
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    Correlation between helium mole fraction and plasma bullet propagation in low temperature plasma jets (2010)
    Institute of Physics
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    Publication Date: 2010-03-30
    Print ISSN: 0022-3727
    Electronic ISSN: 1361-6463
    Topics: Physics
    Published by Institute of Physics
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  • 6
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    Experimental investigations of plasma bullets (2009)
    Institute of Physics
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    Publication Date: 2009-02-16
    Print ISSN: 0022-3727
    Electronic ISSN: 1361-6463
    Topics: Physics
    Published by Institute of Physics
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