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- EMDB-61580: Human Glycine Transporter 1 in the Apo State with an Outward-Faci... -

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Basic information

Entry
Database: EMDB / ID: EMD-61580
TitleHuman Glycine Transporter 1 in the Apo State with an Outward-Facing Conformation
Map data
Sample
  • Complex: human glycine transporter 1 (GlyT1)
    • Protein or peptide: Isoform GlyT-1B of Sodium- and chloride-dependent glycine transporter 1
Keywordshuman glycine transporter 1 / GlyT1 / apo / MEMBRANE PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 6.05 Å
AuthorsWei Y / Li N / Li R / Zhao Y
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)92157102 China
CitationJournal: Nat Commun / Year: 2025
Title: Modulation of the human GlyT1 by clinical drugs and cholesterol.
Authors: Na Li / Yiqing Wei / Renjie Li / Yufei Meng / Jun Zhao / Qinru Bai / Gang Wang / Yan Zhao /
Abstract: Glycine transporter 1 (GlyT1) is a key player in shaping extracellular glutamatergic signaling processes and holds promise for treating cognitive impairments associated with schizophrenia by ...Glycine transporter 1 (GlyT1) is a key player in shaping extracellular glutamatergic signaling processes and holds promise for treating cognitive impairments associated with schizophrenia by inhibiting its activity and thus enhancing the function of NMDA receptors. Despite its significant role in physiological and pharmacology, its modulation mechanism by clinical drugs and internal lipids remains elusive. Here, we determine cryo-EM structures of GlyT1 in its apo state and in complex with clinical trial drugs iclepertin and sarcosine. The GlyT1 in its apo state is determined in three distinct conformations, exhibiting a conformational equilibrium of the transport cycle. The complex structures with inhibitor iclepertin and sarcosine elucidate their unique binding poses with GlyT1. Three binding sites of cholesterol are determined in GlyT1, two of which are conformation-dependent. Transport kinetics studies reveal that a delicate binding equilibrium for cholesterol is crucial for the conformational transition of GlyT1. This study significantly enhances our understanding of the physiological and pharmacological aspects of GlyT1.
History
DepositionSep 18, 2024-
Header (metadata) releaseMar 5, 2025-
Map releaseMar 5, 2025-
UpdateMar 26, 2025-
Current statusMar 26, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_61580.png

Downloads & links

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Map

FileDownload / File: emd_61580.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 256 pix.
= 272. Å		1.06 Å/pix.
x 256 pix.
= 272. Å		1.06 Å/pix.
x 256 pix.
= 272. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.0625 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.5
Minimum - Maximum-0.5527117 - 1.1895673
Average (Standard dev.)-0.0005406298 (±0.023747591)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 272.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_61580_half_map_1.map
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: #2

Fileemd_61580_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : human glycine transporter 1 (GlyT1)

EntireName: human glycine transporter 1 (GlyT1)
Components
  • Complex: human glycine transporter 1 (GlyT1)
    • Protein or peptide: Isoform GlyT-1B of Sodium- and chloride-dependent glycine transporter 1

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Supramolecule #1: human glycine transporter 1 (GlyT1)

SupramoleculeName: human glycine transporter 1 (GlyT1) / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Isoform GlyT-1B of Sodium- and chloride-dependent glycine transpo...

MacromoleculeName: Isoform GlyT-1B of Sodium- and chloride-dependent glycine transporter 1
type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
SequenceString: MSGGDTRAAI ARPRMAAAHG PVAPSSPEQN GAVPSEATKR DQNLKRGNWG NQIEFVLTSV GYAVGLGNVW RFPYLCYRNG GGAFMFPYFI MLIFCGIPLF FMELSFGQFA SQGCLGVWRI SPMFKGVGYG MMVVSTYIGI YYNVVICIAF YYFFSSMTHV LPWAYCNNPW ...String:
MSGGDTRAAI ARPRMAAAHG PVAPSSPEQN GAVPSEATKR DQNLKRGNWG NQIEFVLTSV GYAVGLGNVW RFPYLCYRNG GGAFMFPYFI MLIFCGIPLF FMELSFGQFA SQGCLGVWRI SPMFKGVGYG MMVVSTYIGI YYNVVICIAF YYFFSSMTHV LPWAYCNNPW NTHDCAGVLD ASNLTNGSRP AALPSNLSHL LNHSLQRTSP SEEYWRLYVL KLSDDIGNFG EVRLPLLGCL GVSWLVVFLC LIRGVKSSGK VVYFTATFPY VVLTILFVRG VTLEGAFDGI MYYLTPQWDK ILEAKVWGDA ASQIFYSLGC AWGGLITMAS YNKFHNNCYR DSVIISITNC ATSVYAGFVI FSILGFMANH LGVDVSRVAD HGPGLAFVAY PEALTLLPIS PLWSLLFFFM LILLGLGTQF CLLETLVTAI VDEVGNEWIL QKKTYVTLGV AVAGFLLGIP LTSQAGIYWL LLMDNYAASF SLVVISCIMC VAIMYIYGHR NYFQDIQMML GFPPPLFFQI CWRFVSPAII FFILVFTVIQ YQPITYNHYQ YPGWAVAIGF LMALSSVLCI PLYAMFRLCR TDGDTLLQRL KNATKPSRDW GPALLEHRTG RYAPTIAPSP EDGFEVQPLH PDKAQIPIVG SNGSSRLQDS RI

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOCONTINUUM (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 6.05 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 9711
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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