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Structure paper

TitleMechanism of conductance control and neurosteroid binding in NMDA receptors.
Journal, issue, pagesNature, Vol. 648, Issue 8092, Page 220-228, Year 2025
Publish dateOct 29, 2025
AuthorsHyunook Kang / Ruben Steigerwald / Elijah Z Ullman / Max Epstein / Srinu Paladugu / Dennis C Liotta / Stephen F Traynelis / Hiro Furukawa /
PubMed AbstractIon-channel activity reflects a combination of open probability and unitary conductance. Many channels display subconductance states that modulate signalling strength, yet the structural mechanisms ...Ion-channel activity reflects a combination of open probability and unitary conductance. Many channels display subconductance states that modulate signalling strength, yet the structural mechanisms governing conductance levels remain incompletely understood. Here we report that conductance levels are controlled by the bending patterns of pore-forming transmembrane helices in the heterotetrameric neuronal channel GluN1a-2B N-methyl-D-aspartate receptor (NMDAR). Our single-particle electron cryomicroscopy (cryo-EM) analyses demonstrate that an endogenous neurosteroid and synthetic positive allosteric modulator (PAM), 24S-hydroxycholesterol (24S-HC), binds to a juxtamembrane pocket in the GluN2B subunit and stabilizes the fully open-gate conformation, where GluN1a M3 and GluN2B M3' pore-forming helices are bent to dilate the channel pore. By contrast, EU1622-240 binds to the same GluN2B juxtamembrane pocket and a distinct juxtamembrane pocket in GluN1a to stabilize a sub-open state whereby only the GluN2B M3' helix is bent. Consistent with the varying extents of gate opening, the single-channel recordings predominantly show full-conductance and subconductance states in the presence of 24S-HC and EU1622-240, respectively. Another class of neurosteroid, pregnenolone sulfate, engages a similar GluN2B pocket, but two molecules bind simultaneously, revealing a diverse neurosteroid recognition pattern. Our study identifies that the juxtamembrane pockets are critical structural hubs for modulating conductance levels in NMDAR.
External linksNature / PubMed:41162707
MethodsEM (single particle)
Resolution2.84 - 3.34 Å
Structure data

EMDB-70644: Consensus map of open state Gly/Glu/24S-HC bound hGluN1a-2B NMDAR
Method: EM (single particle) / Resolution: 3.15 Å

EMDB-70645: ECD focused map of open state Gly/Glu/24S-HC bound hGluN1a-2B NMDAR
Method: EM (single particle) / Resolution: 3.12 Å

EMDB-70646: TMD focused refined open state Gly/Glu/24S-HC bound hGluN1a-2B NMDAR
Method: EM (single particle) / Resolution: 3.13 Å

EMDB-70647: Consensus map of Closed state Gly/Glu/24S-HC bound hGluN1a-2B NMDAR
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-70648: TMD focus refined Closed state Gly/Glu/24S-HC bound hGluN1a-2B NMDAR
Method: EM (single particle) / Resolution: 3.05 Å

EMDB-70649: ECD focus refined map of Closed state Gly/Glu/24S-HC bound hGluN1a-2B NMDAR
Method: EM (single particle) / Resolution: 3.13 Å

EMDB-70650: Consensus map of Non-active state Gly/Glu/PS bound hGluN1a-2B NMDAR
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-70651: ECD focus refined map of Non-active state Gly/Glu/PS bound hGluN1a-2B NMDAR
Method: EM (single particle) / Resolution: 2.84 Å

EMDB-70652: TMD focus refined map of Non-active state Gly/Glu/PS bound hGluN1a-2B NMDAR
Method: EM (single particle) / Resolution: 2.89 Å

EMDB-70653: Consensus map of pre-active state Gly/Glu/PS bound hGluN1a-2B NMDAR
Method: EM (single particle) / Resolution: 3.13 Å

EMDB-70654: ECD focus refined map of preactive state Gly/Glu/PS bound hGluN1a-2B NMDAR
Method: EM (single particle) / Resolution: 3.13 Å

EMDB-70655: TMD focus refined map of preactive state Gly/Glu/PS bound hGluN1a-2B NMDAR
Method: EM (single particle) / Resolution: 3.07 Å

70669

9ooq

EMDB-70669, PDB-9ooq:
Closed state of Gly/Glu/24S-HC bound hGluN1a-2B NMDAR
Method: EM (single particle) / Resolution: 3.2 Å

70670

9oor

EMDB-70670, PDB-9oor:
Open state Gly/Glu/24S-HC bound hGluN1a-2B NMDAR
Method: EM (single particle) / Resolution: 3.15 Å

70671

9oos

EMDB-70671, PDB-9oos:
Non-active state of Gly/Glu/Pregnenolone Sulfate bound hGluN1a-2B NMDAR
Method: EM (single particle) / Resolution: 3.03 Å

70672

9oot

EMDB-70672, PDB-9oot:
Pre-active state of Gly/Glu/Pregnenolone Sulfate bound hGluN1a-2B NMDAR
Method: EM (single particle) / Resolution: 3.13 Å

70673

9oou

EMDB-70673, PDB-9oou:
Glycine/Glutamate/EU 1622-240 rGluN1a-2B NMDAR
Method: EM (single particle) / Resolution: 3.34 Å

Chemicals

ChemComp-GLY:
GLYCINE

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM

ChemComp-GLU:
GLUTAMIC ACID

PDB-1ce1:
1.9A STRUCTURE OF THE THERAPEUTIC ANTIBODY CAMPATH-1H FAB IN COMPLEX WITH A SYNTHETIC PEPTIDE ANTIGEN

ChemComp-HOH:
WATER

ChemComp-A8W:
Pregnenolone sulfate

PDB-1aft:
SMALL SUBUNIT C-TERMINAL INHIBITORY PEPTIDE OF MOUSE RIBONUCLEOTIDE REDUCTASE AS BOUND TO THE LARGE SUBUNIT, NMR, 26 STRUCTURES

ChemComp-CLR:
CHOLESTEROL

Source
  • homo sapiens (human)
  • rattus norvegicus (Norway rat)
KeywordsMEMBRANE PROTEIN / N-methyl-D-aspartate receptor / Closed state / 24S-HC / GluN2B / Open state / Non-active / Pregnenolone Sulfate / pre-active / Ion Channels / NMDAR

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