9XCA

CryoEM structure of the G6PT dimer

Summary for 9XCA

• Entry DOI: 10.2210/pdb9xca/pdb
• EMDB information: 66727
• Descriptor: Glucose-6-phosphate exchanger SLC37A4, Lauryl Maltose Neopentyl Glycol (2 entities in total)
• Functional Keywords: glucose-6-phosphate translocase, g6pt, slc37a4, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 100061.59

Authors

Zhang, W.Q.,Jiao, H.Z.,Hu, H.L.,Guo, X. (deposition date: 2025-10-25, release date: 2026-03-18, Last modification date: 2026-09-30)

Primary citation

Zhang, W.,Jiao, H.,Xue, J.,Zhou, J.,Wang, Y.,Pan, Q.,Guo, Y.,Zhang, G.,Hu, H.,Guo, X.
Structures of the human glucose-6-phosphate transporter provide insights into its transport cycle and substrate recognition.
Plos Biol., 24:e3003731-e3003731, 2026

PubMed Abstract: The human glucose-6-phosphate transporter (G6PT/SLC37A4) mediates the translocation of glucose-6-phosphate (G6P) from the cytoplasm into the endoplasmic reticulum, a process essential for glucose production and the maintenance of blood glucose homeostasis between meals. Dysfunction of G6PT causes glycogen storage disease type Ib (GSD-Ib), a severe metabolic disorder characterized by hypoglycemia, hepatomegaly, and neutropenia. Despite its physiological and clinical significance, the structural basis of G6P recognition and the molecular mechanisms underlying GSD-Ib have remained elusive. Here, we present cryo-electron microscopy structures of human G6PT, revealing a monomer in an outward-open state at 3.1 Å and a homodimeric assembly in a face-to-face topology at 3.3 Å. By combining computational modeling of the G6P-G6PT complexes with functional characterization, we have uncovered the key molecular elements that govern the alternating-access mechanism: an electropositive substrate-binding pocket tailored for phosphorylated sugars; conserved aromatic residues that seal the cytosolic gate; and a dynamic inter-domain salt bridge that regulates the conformational transition. Our work provides fundamental insights into the transport cycle of the organophosphate:phosphate antiporter (OPA) family, offers a framework for interpreting GSD-Ib pathology at the molecular level, and establishes a foundation for advancing the mechanistic understanding of the human SLC37 family.

PubMed: 41911224
DOI: 10.1371/journal.pbio.3003731

Experimental method

ELECTRON MICROSCOPY (3.27 Å)