9W1O

Phosphate-bound human SLC37A4 antiparallel dimer

Summary for 9W1O

• Entry DOI: 10.2210/pdb9w1o/pdb
• EMDB information: 65552
• Descriptor: Glucose-6-phosphate exchanger SLC37A4, PHOSPHATE ION (2 entities in total)
• Functional Keywords: slc37a4, g6pt, g6p, phosphate, gsd-ib, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 95320.18

Authors

Zhou, D.,Zhang, Z. (deposition date: 2025-07-26, release date: 2025-11-19, Last modification date: 2025-11-26)

Primary citation

Zhou, D.,Zhang, Y.,Chen, N.,Huang, S.,Song, C.,Zhang, Z.
Structural basis of G6P/Pi transport and inhibition in SLC37A4.
Nat.Struct.Mol.Biol., 2025

PubMed Abstract: 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.

PubMed: 41225049
DOI: 10.1038/s41594-025-01711-5

Experimental method

ELECTRON MICROSCOPY (3.2 Å)