7eu7
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[7eu7]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7EU7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7EU7 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7eu7]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7EU7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7EU7 FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GLU:GLUTAMIC+ACID'>GLU</scene>, <scene name='pdbligand=GLY:GLYCINE'>GLY</scene>, <scene name='pdbligand=JC9:(2~{S})-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one'>JC9</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.5Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GLU:GLUTAMIC+ACID'>GLU</scene>, <scene name='pdbligand=GLY:GLYCINE'>GLY</scene>, <scene name='pdbligand=JC9:(2~{S})-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one'>JC9</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7eu7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7eu7 OCA], [https://pdbe.org/7eu7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7eu7 RCSB], [https://www.ebi.ac.uk/pdbsum/7eu7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7eu7 ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7eu7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7eu7 OCA], [https://pdbe.org/7eu7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7eu7 RCSB], [https://www.ebi.ac.uk/pdbsum/7eu7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7eu7 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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Ketamine is a non-competitive channel blocker of N-methyl-D-aspartate (NMDA) receptors(1). A single sub-anaesthetic dose of ketamine produces rapid (within hours) and long-lasting antidepressant effects in patients who are resistant to other antidepressants(2,3). Ketamine is a racemic mixture of S- and R-ketamine enantiomers, with S-ketamine isomer being the more active antidepressant(4). Here we describe the cryo-electron microscope structures of human GluN1-GluN2A and GluN1-GluN2B NMDA receptors in complex with S-ketamine, glycine and glutamate. Both electron density maps uncovered the binding pocket for S-ketamine in the central vestibule between the channel gate and selectivity filter. Molecular dynamics simulation showed that S-ketamine moves between two distinct locations within the binding pocket. Two amino acids-leucine 642 on GluN2A (homologous to leucine 643 on GluN2B) and asparagine 616 on GluN1-were identified as key residues that form hydrophobic and hydrogen-bond interactions with ketamine, and mutations at these residues reduced the potency of ketamine in blocking NMDA receptor channel activity. These findings show structurally how ketamine binds to and acts on human NMDA receptors, and pave the way for the future development of ketamine-based antidepressants. | Ketamine is a non-competitive channel blocker of N-methyl-D-aspartate (NMDA) receptors(1). A single sub-anaesthetic dose of ketamine produces rapid (within hours) and long-lasting antidepressant effects in patients who are resistant to other antidepressants(2,3). Ketamine is a racemic mixture of S- and R-ketamine enantiomers, with S-ketamine isomer being the more active antidepressant(4). Here we describe the cryo-electron microscope structures of human GluN1-GluN2A and GluN1-GluN2B NMDA receptors in complex with S-ketamine, glycine and glutamate. Both electron density maps uncovered the binding pocket for S-ketamine in the central vestibule between the channel gate and selectivity filter. Molecular dynamics simulation showed that S-ketamine moves between two distinct locations within the binding pocket. Two amino acids-leucine 642 on GluN2A (homologous to leucine 643 on GluN2B) and asparagine 616 on GluN1-were identified as key residues that form hydrophobic and hydrogen-bond interactions with ketamine, and mutations at these residues reduced the potency of ketamine in blocking NMDA receptor channel activity. These findings show structurally how ketamine binds to and acts on human NMDA receptors, and pave the way for the future development of ketamine-based antidepressants. | ||
| - | Structural basis of ketamine action on human NMDA receptors.,Zhang Y, Ye F, Zhang T, Lv S, Zhou L, Du D, Lin H, Guo F, Luo C, Zhu S Nature. 2021 Aug;596(7871):301-305. doi: 10.1038/s41586-021-03769-9. Epub 2021, Jul 28. PMID:34321660<ref>PMID:34321660</ref> | + | Structural basis of ketamine action on human NMDA receptors.,Zhang Y, Ye F, Zhang T, Lv S, Zhou L, Du D, Lin H, Guo F, Luo C, Zhu S Nature. 2021 Aug;596(7871):301-305. doi: 10.1038/s41586-021-03769-9. Epub 2021 , Jul 28. PMID:34321660<ref>PMID:34321660</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 7eu7" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 7eu7" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Glutamate receptor 3D structures|Glutamate receptor 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
Current revision
Structure of the human GluN1-GluN2A NMDA receptor in complex with S-ketamine, glycine and glutamate
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