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TitleStructural basis of G6P/Pi transport and inhibition in SLC37A4.
Journal, issue, pagesNat Struct Mol Biol, Year 2025
Publish dateNov 12, 2025
AuthorsDong Zhou / Yang Zhang / Nanhao Chen / Shitang Huang / Chen Song / Zhe Zhang /
PubMed AbstractGlycogen storage disease type Ib (GSD-Ib), caused by loss-of-function mutations in the endoplasmic reticulum transporter SLC37A4, disrupts glucose homeostasis through impaired glucose-6-phosphate ...Glycogen storage disease type Ib (GSD-Ib), caused by loss-of-function mutations in the endoplasmic reticulum transporter SLC37A4, disrupts glucose homeostasis through impaired glucose-6-phosphate (G6P)/phosphate (Pi) antiport. Despite its central role in glycogen metabolism and immune regulation, the structural mechanisms governing SLC37A4's transport cycle and pathological dysfunction remain elusive. Here we report cryo-electron microscopy structures of human SLC37A4 in four functional states, capturing conformational transitions between lumen-facing and cytoplasm-facing states. Combined with mutational analysis, molecular dynamics simulations and functional assays, we identify a conserved substrate-binding pocket that alternately accommodates G6P and Pi through electrostatic complementarity and domain-dependent interactions. We further demonstrate that the high-affinity inhibitor S-4048 sterically occludes the cytoplasmic entry pathway by trapping the transporter in a cytoplasm-facing conformation. Our work elucidates the molecular pathology of GSD-Ib-linked mutations and provides a structural framework for developing therapies targeting this transporter in metabolic diseases.
External linksNat Struct Mol Biol / PubMed:41225049
MethodsEM (single particle)
Resolution3.2 - 3.4 Å
Structure data

65551

9w1n

EMDB-65551, PDB-9w1n:
Human SLC37A4 antiparallel dimer
Method: EM (single particle) / Resolution: 3.2 Å

65552

9w1o

EMDB-65552, PDB-9w1o:
Phosphate-bound human SLC37A4 antiparallel dimer
Method: EM (single particle) / Resolution: 3.2 Å

65553

9w1p

EMDB-65553, PDB-9w1p:
G6P-bound human SLC37A4 lateral dimer
Method: EM (single particle) / Resolution: 3.4 Å

65554

9w1q

EMDB-65554, PDB-9w1q:
Human SLC37A4 lateral dimer
Method: EM (single particle) / Resolution: 3.2 Å

65555

9w1r

EMDB-65555, PDB-9w1r:
S-4048-bound human SLC37A4 monomer
Method: EM (single particle) / Resolution: 3.4 Å

Chemicals

ChemComp-PO4:
PHOSPHATE ION

ChemComp-G6P:
6-O-phosphono-alpha-D-glucopyranose

PDB-1eup:
X-RAY CRYSTAL STRUCTURE OF CYTOCHROME P450ERYF WITH ANDROSTENDIONE BOUND

Source
  • homo sapiens (human)
  • escherichia coli (E. coli)
KeywordsTRANSPORT PROTEIN / SLC37A4 / G6PT / G6P / GSD-Ib / Phosphate / S-4048

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