9W1N: Human SLC37A4 ER-membrane glucose-6-phosphate/phosphate antiporter, in its apo, lumen-facing conformation

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Function

9W1N captures SLC37A4 in its lumen-facing, substrate-free conformation, representing the starting point of the G6P/Pi exchange cycle. The central cavity is open toward the ER lumen and sealed on the cytosolic side, consistent with a transporter ready to release Pi or to bind luminal factors.

This state provides the template for how the transporter organises a pre-formed phosphate pocket before substrate binds.

Disease

9W1N reveals the positions of conserved Lys/His residues (K29, K64, H366) forming the phosphate-binding hotspot; many GSD-Ib mutations map directly onto this region.

The apo structure reveals how even small perturbations of the substrate cavity or cytoplasmic gate can disrupt the correct lumen-open geometry, explaining loss-of-function phenotypes.

Several pathogenic variants cluster at the dimer interface surfaces, clearly visualised in 9W1N.

Relevance

9W1N is the reference architecture for all other SLC37A4 structures, Pi-bound (9W1O), G6P-bound (9W1P), lateral dimers, and the inhibitor-bound cytosol-open state (9W1R).

It defines the resting, lumen-open gate essential for understanding how substrates gain access to the ER-facing cavity, how is antiport asymmetry maintained and which structural elements move during transport.

Serves as a baseline for comparing disease mutations, substrate recognition, and inhibitor locking.

Structural highlights

State captured is apo, lumen-facing, antiparallel dimer (C2 symmetry). Resolution: ~3.2 Å cryo-EM, allowing accurate visualisation of the central cavity, gates, and conserved charged residues.

It has a unique dimer architecture, with antiparallel packing of the two protomers. The interface is tight but still allows for large-scale rearrangements, as seen in lateral dimers.

Cavity features are that it has a positively charged, pre-shaped phosphate pocket despite the absence of a ligand. The residues K29, K64, M145, and H366 are positioned for immediate substrate coordination.

The cytosolic gate has closed-TM helices pack to block access. The luminal gate is open, showing a clear solvent-accessible path. This represents the lumen-access state in the alternating-access cycle.

It also serves as the structural endpoint opposite the cytosol-open inhibitor-bound structure (9W1R).

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