Structural Mechanism of N-Methyl-D-Aspartate Receptor Type 1 Partial Agonism

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dc.contributor.author Ylilauri, Mikko
dc.contributor.author Pentikäinen, Olli
dc.date.accessioned 2012-10-23T04:51:43Z
dc.date.available 2012-10-23T04:51:43Z
dc.date.issued 2012
dc.identifier.citation Ylilauri, M., & Pentikäinen, O. (2012). Structural Mechanism of N-Methyl-D-Aspartate Receptor Type 1 Partial Agonism. PLoS One, 7 (10), e47604. doi:10.1371/journal.pone.0047604 Retrieved from http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047604 fi
dc.identifier.issn 1932-6203
dc.identifier.other TUTKAID_52480
dc.identifier.uri http://hdl.handle.net/123456789/40059
dc.description.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. fi
dc.language.iso eng
dc.publisher PLOS
dc.relation.ispartof PLoS One
dc.relation.uri http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047604
dc.rights © 2012 Ylilauri, Pentikäinen. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.subject.other glutamaattireseptori fi
dc.subject.other partiaalinen agonisti fi
dc.subject.other molekyylidynamiikka fi
dc.subject.other glutamate receptor en
dc.subject.other partial agonist en
dc.subject.other molecular dynamics en
dc.title Structural Mechanism of N-Methyl-D-Aspartate Receptor Type 1 Partial Agonism
dc.type Article en
dc.identifier.urn URN:NBN:fi:jyu-201210232753
dc.subject.kota 116, 1182, 3111, 3112
dc.contributor.laitos Department of Biological and Environmental Science en
dc.contributor.laitos Bio- ja ympäristötieteiden laitos fi
dc.contributor.oppiaine solu- ja molekyylibiologia fi
jyx.tutka.volyme 7
jyx.tutka.mnumber 10
jyx.tutka.pagetopage e47604
dc.type.uri http://purl.org/eprint/type/JournalArticle
dc.identifier.doi 10.1371/journal.pone.0047604
dc.date.updated 2012-10-23T03:30:03Z
dc.description.version Publisher's PDF
eprint.status http://purl.org/eprint/type/status/PeerReviewed

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