Tian M , Stroebel D , Piot L , David M , Ye S , Paoletti P .

	Fig. 1. NTD heterodimer photocrosslinking locks GluN2B receptors in a high Po mode.a Structure of the full-length GluN1/GluN2B receptor in the inhibited state (side view; PDB 4PE5, Ref. 10 and see “Methods”). The receptor, composed of two GluN1 subunits and two GluN2B subunits, assembles as a dimer-of-dimers and display a layered arrangement (NTD, LBD, TMD). The two front subunits are shown in cartoon representation while the two subunits in the back are displayed in space-filled. NTD N-terminal domain, LBD ligand-binding domain also named agonist-binding domain, TMD transmembrane domain. Inset: enlargement of the GluN1-GluN2B NTD heterodimer lower lobe region. Residues in GluN1 and GluN2B subunits subjected to amber mutation (allowing incorporation of photo-cross-linker amino acids) are represented as sticks. b Representative current traces from oocytes expressing GluN1-K178AzF/GluN2B mutant (left) and wild-type (wt, right) receptors during UV illumination (365 nm) in the presence (top) or absence (bottom) of agonists. ago, for agonists (glutamate and glycine, 100 µM each). c Change in current amplitude upon UV illumination (Iuv/Io) of wild-type (wt) GluN1/GluN2B receptors and various GluN1-AzF/GluN2B mutant receptors. Values are: 1.04 ± 0.09 (n = 16) for wt, 1.65 ± 0.12 (n = 5) for GluN1-R174AzF, 4.39 ± 1.40 (n = 37) for GluN1-K178AzF, 1.51 ± 0.26 (n = 25) for GluN1-T182AzF and 1.19 ± 0.13 (n = 4) for GluN1-E185AzF. Data represent mean ± SD. n = number of biologically independent cells. *P = 0.011, ***P < 0.001 (one-way ANOVA). d Change in current amplitude upon UV illumination (Iuv/Io) of wt and GluN1-K178AzF/GluN2B mutant receptors during (+ago) or between (−ago) agonist application. Values are, from left to right: 1.04 ± 0.09 (n = 16) for wt +ago; 1.00 ± 0.07 (n = 14) for wt −ago; 4.39 ± 1.40 (n = 37) for mutant +ago; 5.05 ± 1.73 (n = 23) for mutant −ago. Data represent mean ± SD. n = number of biologically independent cells. ***P < 0.001, n.s. non-significant (P = 0.25 for wt ± ago, and 0.11 for GluN1-K178AzF ± ago) (one-way ANOVA). e Assessment of receptor channel activity using MK-801 inhibition kinetics. MK-801 kon values were normalized to the mean value obtained with wild-type (wt) GluN1/GluN2B receptors. Relative values are, from left to right: 0.57 ± 0.13, (n = 19) without UV and 1.45 ± 0.38 (n = 9) with UV for GluN1-K178AzF/GluN2B; 1.00 ± 0.15 (n = 23) for wt (no UV). Inset: representative scaled current traces from oocytes expressing wild-type (dashed) or GluN1-K178AzF/GluN2B receptors before (black) and after (violet) UV illumination in response to 50 nM MK-801. Data represent mean ± SD. n = number of biologically independent cells. ***P < 0.001 (one-way ANOVA). f Immunoblots from HEK cells expressing GluN1-K178AzF/GluN2B mutant receptors and exposed to UV (+) or not (−). Samples were analyzed using anti-GluN1 and anti-Strep antibodies. GluN1 monomer (M1) is expected to run at ~110 kDa, GluN2B-Strep monomer (M2) at ~130 kDa, and GluN1/GluN2B heterodimer (D1/2) at ~240 kDa. “IP: Strep” indicates the treatment with an immuno-purification procedure using the Strep tag.
	Fig. 2. Photopotentiation necessitates inter-subunit mobility of the GluN1/GluN2B NTD heterodimer.a Location of each double cysteine mutations (CC) in the GluN1/GluN2B NTD heterodimer (PDB 4PE5, Ref. 10). Mutant receptors are GluN1-K178AzF/GluN2B-A135C-P177C (2B-CC), GluN1-S126C-H171C-K178AzF/GluN2B wt (N1-CC) and GluN1-K178AzF-L320C/GluN2B-D210C (N1-C/2B-C). Introduced cysteines are highlighted as yellow spheres and the GluN1-K178 position as red spheres. b Responsiveness of disulfide-bond linked mutant receptors to UV illumination (365 nm). Representative current traces measured from oocytes expressing wild-type (wt) or various cysteine mutant receptors (as described in a) during UV illumination. Note that the UV-induced potentiation is almost completely lost on receptors with inter-subunit disulfide bond cross-linked NTDs (N1C/2B-C). ago, for agonists (glutamate and glycine, 100 µM each). c Change in current amplitude upon UV illumination (Iuv/Io) of wild-type (wt) GluN1/GluN2B receptors and cysteine mutant receptors (as described in a). Values are: 1.04 ± 0.09 (n = 16) for wt, 4.39 ± 1.40 (n = 37) for GluN1-K178AzF/GluN2B, 2.52 ± 0.21 (n = 3) for 2B-CC, 1.63 ± 0.29 (n = 9) for N1-CC and 1.12 ± 0.10 (n = 8) for N1-C/2B-C. Bottom cartoons illustrate the introduced disulfide bond pair and their impact on NTD clamshell closure. Data represent mean ± SD. n = number of biologically independent cells. *P = 0.030, ***P < 0.001 (one-way ANOVA).
	Fig. 3. Photocrosslinking differentially affects allosteric modulation of GluN2A and GluN2B receptors.a Representative current traces from oocytes expressing GluN1-K178AzF/GluN2A receptors (top traces) and GluN1-K178/GluN2B receptors (bottom traces) during UV illumination. Experiments were performed at pH 7.3 (left, black) or pH 6.5 (right, blue). ago, for agonists. Inset: immunoblots from HEK cells expressing GluN1-K178AzF/GluN2A-Strep mutant receptors and exposed to UV (+) or not (−) at pH 6.5 or 7.3. GluN2A-Strep monomer (M2) is expected to run at ~130 kDa, and GluN1/GluN2A heterodimer (D1/2) at ~240 kDa. b Change in current amplitude upon UV illumination (Iuv/Io) of wild-type (wt) receptors and GluN1-K178AzF/GluN2A and GluN1-K178azF/GluN2B mutant receptors, recorded either at pH 7.3 or 6.5. Values are, from left to right: 1.45 ± 0.23 (n = 32) and 1.23 ± 0.37 (n = 58) for AzF mutant GluN2A receptors; 1.09 ± 0.10 (n = 10) and 1.04 ± 0.07 (n = 12) for wt GluN2A receptors; 4.39 ± 1.40 (n = 37) and 8.59 ± 3.71 (n = 41) for AzF mutant GluN2B receptors; 1.04 ± 0.09 (n = 16) and 1.14 ± 0.09 (n = 4) for wt GluN2B receptors. Data represent mean ± SD. n = number of biologically independent cells. **P = 0.004, ***P < 0.001, n.s. non-significant (P = 0.22 for wt GluN2A and 0.06 for wt GluN2B) (one-way ANOVA). c Zinc sensitivity of GluN1-K178AzF/GluN2A receptors (left) and GluN1-K178/GluN2B receptors (right), before (plain black line) and after (violet) UV treatment. Dashed line, wt receptors; dotted line, GluN2-ΔNTD receptors80. Values of Zn2+ IC50, maximal inhibition (for GluN2A receptors) and Hill slope (nH) are: 7.43 ± 1.10 nM, 0.70 ± 0.03 and 0.99 ± 0.09 (n = 4) before UV, and 7.69 ± 0.17 nM, 0.52 ± 0.04 and 1.05 ± 0.07 (n = 3) after UV for GluN1-K178AzF/GluN2A; 15.33 ± 2.99 nM, 0.74 ± 0.05 and 0.70 ± 0.03 (n = 4) for wt GluN1/GluN2A; 0.54 ± 0.01 μM and 1.02 ± 0.02 (n = 4) before UV, and 7.96 ± 0.16 µM and 0.91 ± 0.02 (n = 3) after UV for GluN1-K178AzF/GluN2B; 0.72 ± 0.03 μM and 1.08 ± 0.04 (n = 4) for wt GluN1/GluN2B. Data represent mean ± SD. n = number of biologically independent cells. d Proton sensitivity. Conditions as in c. Values of pHIC50 and Hill slope (nH) are: 7.00 ± 0.02 and 1.91 ± 0.11 (n = 9) before UV, and 7.01 ± 0.01 and 1.93 ± 0.07 (n = 10) after UV for GluN1-K178AzF/GluN2A; 7.60 ± 0.01 and 1.37 ± 0.05 (n = 7–9) before UV; and 6.90 ± 0.02 and 0.99 ± 0.03 (n = 5–6) after UV for GluN1-K178AzF/GluN2B. Data represent mean ± SD. n = number of biologically independent cells. e Ifenprodil sensitivity of GluN1-K178AzF/GluN2B receptors before (plain black line) and after (violet) UV treatment. Dashed line, wt GluN1/GluN2B receptors. Values of ifenprodil IC50, maximal inhibition and Hill slope (nH) are: 0.32 ± 0.02 µM, 0.95 ± 0.02 and 1.22 ± 0.04 (n = 3) for wt; 0.24 ± 0.06 µM, 0.98 ± 0.09 and 1.25 ± 0.39 (n = 4) before UV; and 0.40 ± 0.12 µM, 0.54 ± 0.06 and 1.25 ± 0.11 (n = 4) after UV for GluN1-K178AzF/GluN2B. Data represent mean ± SD. n = number of biologically independent cells. f Spermine sensitivity. Conditions as in e. Values of spermine EC50, maximal potentiation and nH are: 174.3 ± 64.5 μM, 11.2 ± 3.3 and 1.26 ± 0.09 (n = 3–5) for wt; 214.9 ± 63.2 μM, 26.1 ± 2.5 and 1.29 ± 0.22 (n = 4) before UV; and 93.0 ± 22.8 μM, 1.6 ± 0.5 and 1.14 ± 0.16 (n = 5) after UV for GluN1-K178AzF/GluN2B. Data represent mean ± SD. n = number of biologically independent cells.
	Fig. 4. Restraining NTD inter-dimer conformational mobility differentially affects GluN2A and GluN2B allostery.a Structure of the full-length GluN1/GluN2B receptors (inhibited state PDB 4PE5, Ref. 10) with the location of the engineered cysteine mutation highlighted (yellow spheres). The two GluN2 subunits are shown in cartoon representation while the two GluN1 subunits in the back are displayed in space-filled. Inset: enlargement of the region with the pair of cysteines introduced to form a disulfide bond at the NTD inter-dimer interface made by the two adjacent GluN2 NTD lower lobes. b Immunoblots from Xenopus oocytes expressing GluN1/GluN2A-V217C or GluN1/GluN2B-N218C mutant receptors. Samples were analyzed using anti-GluN1 and anti-GluN2A or anti-GluN2B antibodies. GluN1 monomer (M1) runs at ~110 kDa (M1), GluN2A and GluN2B monomer at ~180 kDa (M2), and GluN2 homodimer at ~360 kDa (D2/2). * indicates non-specific background bands. “± β-ME” indicates immunoblots performed with or without β-mercaptoethanol, i.e., in reducing or non-reducing conditions. N.I. for non-injected oocytes. c Zinc inhibition dose-response curves of GluN1/GluN2A-V217C receptors (C-C, plain line). For comparison, zinc sensitivity of wild-type GluN1/GluN2A receptors (wt, dashed line) is also shown. Values of Zn2+ IC50, maximal inhibition and Hill slope (nH) are: 4.64 ± 1.78 nM, 0.40 ± 0.03 and 0.44 ± 0.08 (n = 7–13) for C-C; 12.99 ± 1.12 nM, 0.74 ± 0.01 and 0.77 ± 0.05 (n = 7–18) for wt. Data represent mean ± SD. n = number of biologically independent cells. d Zinc (left) and ifenprodil (right) inhibition dose-response curves of GluN1/GluN2B-N218C receptors (C-C, plain lines). For comparison, zinc and ifenprodil sensitivity of wild-type (wt) GluN1/GluN2B receptors are also shown (dashed lines): Values of Zn2+ IC50 and Hill slope (nH) are: 3.06 ± 0.04 μM and 1.01 ± 0.01 (n = 5) for C-C vs 0.97 ± 0.03 μM and 1.20 ± 0.04 (n = 4) for wt. Values of ifenprodil IC50, maximal inhibition and Hill slope (nH) are: 0.20 ± 0.01 μM, 0.99 ± 0.02 and 1.08 ± 0.06 (n = 5–15) for C-C; 0.13 ± 0.01 μM, 0.95 ± 0.02 and 1.14 ± 0.11 (n = 9–16) for wt. Data represent mean ± SD. n = number of biologically independent cells.
	Fig. 5. Inter-layer NTD-LBD coupling differs between GluN2A and GluN2B receptors.a Structure of the full-length GluN1/GluN2B receptors (inhibited state PDB 4PE5, Ref. 10) with the four engineered cysteine mutations at the LBD intra-dimer interface highlighted (yellow spheres). The NTD binding sites for the negative allosteric modulators ifenprodil and zinc are indicated. Inset: enlargement of the region with cysteines introduced. The binding site for GNE-3419, a GluN2A-selective positive allosteric modulator (PAM) is also highlighted (green spot). b Zinc sensitivity of GluN1-N521C-L777C/GluN2A-E516C-L780C (CC/CC) receptors (plain line). Dashed line, wild-type (wt) GluN1/GluN2A receptors. Values of Zn2+ IC50, maximal inhibition and Hill slope (nH) are: 3.44 ± 2.03 nM, 0.37 ± 0.04 and 0.40 ± 0.11 (n = 4–14) for CC-CC; 12.99 ± 1.12 nM, 0.74 ± 0.01 and 0.77 ± 0.05 (n = 7–18) for wt. Data represent mean ± SD. n = number of biologically independent cells. c Potentiation of wt GluN1/GluN2A receptors by GNE-3419 (100 µM) in the absence or presence of the GluN2A NTD inhibitor zinc (100 nM). Values are: 1.27 ± 0.04 (n = 9) without zinc and 3.01 ± 0.32 (n = 10) in zinc. Inset: Effect of GNE-3419 in the presence of zinc. GNE-3419 application fully reverses zinc inhibition of GluN2A receptors ago, for agonists. Data represent mean ± SD. n = number of biologically independent cells. ***P < 0.001 (two-sided Student’s t test). d Zinc (left) and ifenprodil (right) inhibition dose-response curves of GluN1-N512C-L777C/GluN2B-E517C-L781C receptors (CC-CC, plain lines). Dashed line, wt GluN1/GluN2B receptors. Values of Zn2+ IC50 and Hill slope (nH) are: 0.72 ± 0.05 μM and 0.88 ± 0.05 (n = 4) for CC-CC vs 0.59 ± 0.06 μM and 0.96 ± 0.10 (n = 2–3) for wt. Values of ifenprodil IC50, maximal inhibition and Hill slope (nH) are: 0.17 ± 0.03 μM, 0.76 ± 0.03, nH = 0.83 ± 0.13 (n = 7–8) for CC-CC; 0.15 ± 0.01 μM, 0.93 ± 0.01 and 1.11 ± 0.07 (n = 4–5) for wt. Data represent mean ± SD. n = number of biologically independent cells. e Structure of the full-length GluN1/GluN2B receptors (inhibited state PDB 4PE5, Ref. 10) with the two engineered cysteine mutations at the LBD inter-dimer interface highlighted (yellow spheres). Inset: enlargement of the region with cysteines. f Responsiveness of disulfide-bond linked mutant receptors to UV illumination (365 nm). Left: Representative current traces from oocytes expressing GluN1-K178AzF/GluN2B wt, GluN1-K178AzF-R673C/GluN2B-L795C (N1-C/2B-C) or GluN1-K178AzF-N512C-L777C/GluN2B-E517C-L781C (N1-CC/2B-CC) receptors during UV illumination. ago, for agonists. Right: change in current amplitude upon UV illumination (Iuv/Io) of GluN1-K178AzF/GluN2A wt receptors, GluN1-K178AzF/GluN2B wt receptors, and cysteine mutant receptors. Values are: 1.38 ± 0.15 (n = 8) for GluN1-K178AzF/GluN2A wt; 1.29 ± 0.06 (n = 6) for N1-C/N2A-C (GluN1-K178AzF-R673C/GluN2A-L794C) and 1.18 ± 0.11 (n = 12) for N1-CC/2A-CC; 4.95 ± 1.31 (n = 12) for GluN1-K178AzF/GluN2B wt; 1.68 ± 0.56 (n = 6) for N1-C/N2B-C and 5.17 ± 1.18 (n = 5) for N1-CC/2B-CC. Data represent mean ± SD. n = number of biologically independent cells. *P = 0.034, **P = 0.003, ***P < 0.001, n.s. non-significant (P = 0.21 for GluN2A and 0.75 for GluN2B) (one-way ANOVA).
	Fig. 6. GluN2A and GluN2B receptors exhibit different conformational landscape.Structural analyses were performed using 29 available full-length NMDAR structures. a Lower panel: Localization of the various regions of interest. Letters (c, d and e) indicate the receptor’ regions where structural parameters were measured, and refer to plots in corresponding panels (c, d and e). Upper panel: Zoom of the (d) region encompassing the lower lobes of the GluN1-GluN2 NTD heterodimer. The estimated region for GluN1-K178AzF photocrosslinking is highlighted as a reaction sphere of 9 Å radius from GluN1-K178AzF Cβ57,70. N: reactive nitrene radical, NTD N-terminal domain, LBD ligand-binding domain, TMD transmembrane domain, UL upper lobe, LL lower lobe. b GluN2A and GluN2B receptors differ by their accessibility for inter-subunit cross-linking by the photocrosslinker GluN1-K718AzF. The more atoms lie within the 9 Å of AzF Cβ, the closer are the lower lobes within the NTD heterodimer. Horizontal bars represent mean values. Values of n (number of structures) are (from left to right): 12, 8, 16, 6, 16 and 6. c The NTD intra-dimer upper lobe-upper lobe (UL-UL) interface adopts various compactions in GluN2B, but not GluN2A, receptors. The smaller the value of compaction, the lower the distance between the two UL protomers. Boxes display interquartile range, median is shown as center line, whiskers extend from the hinge to the largest and smallest value no further than plus (upper whisker) or minus (lower whisker) 1.5 x IQR (interquartile range). Values of n (number of structures) are (from left to right): 12, 8, 16, 6, 16 and 6. d The NTD intra-dimer lower lobe-lower lobe (LL) interface displays distinct range of LL separation between GluN2A and GluN2B receptors. Boxes display interquartile range, median is shown as center line, whiskers extend from the hinge to the largest and smallest value no further than plus (upper whisker) or minus (lower whisker) 1.5 x IQR (interquartile range). Values of n (number of structures) are (from left to right): 12, 8, 16, 6, 16 and 6. e The range of LBD inter-dimer rolling motion47 is greater in GluN2B than in GluN2A receptors. Boxes display interquartile range, median is shown as center line, whiskers extend from the hinge to the largest and smallest value no further than plus (upper whisker) or minus (lower whisker) 1.5 x IQR (interquartile range). Values of n (number of structures) are (from left to right): 12, 8, 16, 6, 16 and 6. f NTD-LBD conformational coupling is sampled differently in GluN2A and GluN2B receptors. The graph plots the NTD intra-dimer lower lobe-lower lobe (LL) distance as a function the LBD inter-dimer rolling (parameters described in panels d and e, respectively). The dotted lines correspond to linear regressions for all states of GluN2A (blue, R = 0.725) and GluN2B (red, R = 0.729) receptors. Black arrows indicate the change in level of receptor activity (channel Po), increasing (+) or decreasing (−), according to the receptor conformational state.
	Fig. 7. Long-distance allosteric coupling in GluN2A receptors.a The relationship between the NTD intra-dimer distance and the LBD intra-dimer distance as extracted from 29 available full-length X-ray and cryo-EM NMDAR structures (see “Methods”). Same representation as in Fig. 6f, with blue and red colors for GluN2A and GluN2B receptor structures, respectively, and with an additional GluN2A receptor structure captured in a “splayed open” conformation15 (blue cross). Note that the GluN2A receptor “splayed open” structure displays a disrupted LBD intra-dimer interface but an intact NTD intra-dimer interface. NTD N-terminal domain, LBD ligand-binding domain, UL upper lobe, LL lower lobe. b, c iMODfit simulations on a full-length GluN2A receptor from the “pre-active” state to the “splayed-open” state (2KS-6MMR and SO-6MMI, respectively; Ref. 15). b Evolution of selected collective variable during the iMODFit simulation. The trajectory is segmented into four consecutive steps (I to IV). Displacement values greater than 2 Å or 6 degree angle between the starting and the targeted structures are indicated within the corresponding rectangles. c Conformational changes experienced by the GluN2A receptor when transiting from the “pre-active” to “splayed-open state” (steps I to III). Red arrows represent protein displacements occurring during each step. Circled numbers refer to the collective parameters analyzed in panel (b). Note that during step III, the LBD intra-dimer interface experiences large structural rearrangement eventually leading to its disruption.
	Fig. 8. Proposed mechanisms for inter-layer allosteric transduction in GluN2A and GluN2B receptors.GluN2A and GluN2B receptors utilize different allosteric routes involving differential subunit–subunit interfaces and conformational rearrangements to couple the NTD layer to the downstream gating machinery (LBD + TMD). Middle and upper rows, GluN2A route. Middle and lower rows, GluN2B route. Binding sites for positive and negative allosteric modulators, NAMs and PAMs, respectively, are indicated. Brown arrows within the receptors indicate motions at play during allosteric transduction (left and right arrows for the GluN2B and GluN2A routes, respectively). Note that the NTD intra-dimer interfaces, both at the level of the upper and lower lobes, are known to form sites for allosteric modulators in GluN2B but not GluN2A receptors. In contrast, the LBD inter-dimer interface is known to form sites for allosteric modulators in GluN2A but not GluN2B receptors. See main text (Discussion) for further details. NTD N-terminal domain, LBD ligand-binding domain also named agonist-binding domain, TMD transmembrane domain.

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