TY - JOUR
T1 - Structural basis of subtype-selective competitive antagonism for GluN2C/2D-containing NMDA receptors
AU - Wang, Jue Xiang
AU - Irvine, Mark W.
AU - Burnell, Erica S.
AU - Sapkota, Kiran
AU - Thatcher, Robert J.
AU - Li, Minjun
AU - Simorowski, Noriko
AU - Volianskis, Arturas
AU - Collingridge, Graham L.
AU - Monaghan, Daniel T.
AU - Jane, David E.
AU - Furukawa, Hiro
N1 - Funding Information:
We thank the staff at the 17-ID beamlines at the Brookhaven National Laboratory NSLS-II, in particular Jean Jakoncic, Alexei Soares and Vivian Stojanoff, for help during data collection. This work was funded by NIH (NS111745 and MH085926), Robertson funds at Cold Spring Harbor Laboratory, Doug Fox Alzheimer’s fund, Austin’s purpose, Heartfelt Wing Alzheimer’s fund (to H.F.), NIH (MH060252) (to D.T.M. and D.E.J.), BBSRC (BB/L001977/1) (to D.E.J.) and European Research Council (to G.L.C.). J.X.W. was supported by the George A. & Marjorie H. Anderson Fellowship and a PhD fellowship of the Boehringer Ingelheim Fonds.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - N-Methyl-D-aspartate receptors (NMDARs) play critical roles in the central nervous system. Their heterotetrameric composition generates subtypes with distinct functional properties and spatio-temporal distribution in the brain, raising the possibility for subtype-specific targeting by pharmacological means for treatment of neurological diseases. While specific compounds for GluN2A and GluN2B-containing NMDARs are well established, those that target GluN2C and GluN2D are currently underdeveloped with low potency and uncharacterized binding modes. Here, using electrophysiology and X-ray crystallography, we show that UBP791 ((2S*,3R*)-1-(7-(2-carboxyethyl)phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid) inhibits GluN2C/2D with 40-fold selectivity over GluN2A-containing receptors, and that a methionine and a lysine residue in the ligand binding pocket (GluN2D-Met763/Lys766, GluN2C-Met736/Lys739) are the critical molecular elements for the subtype-specific binding. These findings led to development of UBP1700 ((2S*,3R*)-1-(7-(2-carboxyvinyl)phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid) which shows over 50-fold GluN2C/2D-selectivity over GluN2A with potencies in the low nanomolar range. Our study shows that the l-glutamate binding site can be targeted for GluN2C/2D-specific inhibition.
AB - N-Methyl-D-aspartate receptors (NMDARs) play critical roles in the central nervous system. Their heterotetrameric composition generates subtypes with distinct functional properties and spatio-temporal distribution in the brain, raising the possibility for subtype-specific targeting by pharmacological means for treatment of neurological diseases. While specific compounds for GluN2A and GluN2B-containing NMDARs are well established, those that target GluN2C and GluN2D are currently underdeveloped with low potency and uncharacterized binding modes. Here, using electrophysiology and X-ray crystallography, we show that UBP791 ((2S*,3R*)-1-(7-(2-carboxyethyl)phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid) inhibits GluN2C/2D with 40-fold selectivity over GluN2A-containing receptors, and that a methionine and a lysine residue in the ligand binding pocket (GluN2D-Met763/Lys766, GluN2C-Met736/Lys739) are the critical molecular elements for the subtype-specific binding. These findings led to development of UBP1700 ((2S*,3R*)-1-(7-(2-carboxyvinyl)phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid) which shows over 50-fold GluN2C/2D-selectivity over GluN2A with potencies in the low nanomolar range. Our study shows that the l-glutamate binding site can be targeted for GluN2C/2D-specific inhibition.
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U2 - 10.1038/s41467-020-14321-0
DO - 10.1038/s41467-020-14321-0
M3 - Article
C2 - 31969570
AN - SCOPUS:85078177072
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 423
ER -