9INH

Cryo-EM structure of human XPR1 in complex with InsP6 in outward-facing state (SPX visible)-in the presence of KIDINS220-1-432 and 10 mM KH2PO4

Summary for 9INH

• Entry DOI: 10.2210/pdb9inh/pdb
• EMDB information: 60707
• Descriptor: Solute carrier family 53 member 1, INOSITOL HEXAKISPHOSPHATE, CHOLESTEROL, ... (7 entities in total)
• Functional Keywords: slc53a1, transporter, phosphate, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 177867.78

Authors

Zuo, P.,Liang, L.,Yin, Y. (deposition date: 2024-07-06, release date: 2025-04-02)

Primary citation

Zuo, P.,Wang, W.,Dai, Z.,Zheng, J.,Yu, S.,Wang, G.,Yin, Y.,Liang, L.,Yin, Y.
Synergistic activation of the human phosphate exporter XPR1 by KIDINS220 and inositol pyrophosphate.
Nat Commun, 16:2879-2879, 2025

PubMed Abstract: Inorganic phosphate (Pi) is essential for life, and its intracellular levels must be tightly regulated to avoid toxicity. XPR1, the sole known phosphate exporter, is critical for maintaining this balance. Here we report cryo-EM structures of the human XPR1-KIDINS220 complex in substrate-free closed and substrate-bound outward-open states, as well as an XPR1 mutant in a substrate-bound inward-facing state. In the presence of inositol hexaphosphate (InsP) and phosphate, the complex adopts an outward-open conformation, with InsP binding the SPX domain and juxtamembrane regions, indicating active phosphate export. Without phosphate or InsP, the complex closes, with transmembrane helix 9 blocking the outward cavity and a C-terminal loop obstructing the intracellular cavity. XPR1 alone remains closed even with phosphate and InsP. Functional mutagenesis shows that InsP, whose levels vary with Pi availability, works with KIDINS220 to regulate XPR1 activity. These insights into phosphate regulation may aid in developing therapies for ovarian cancer.

PubMed: 40128258
DOI: 10.1038/s41467-025-58200-y

Experimental method

ELECTRON MICROSCOPY (3.68 Å)