8X5F

human XPR1 in complex with InsP6

Summary for 8X5F

• Entry DOI: 10.2210/pdb8x5f/pdb
• EMDB information: 38068
• Descriptor: Solute carrier family 53 member 1, PHOSPHATE ION, INOSITOL HEXAKISPHOSPHATE, ... (6 entities in total)
• Functional Keywords: transport, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 188925.18

Authors

Jiang, D.H.,Yan, R. (deposition date: 2023-11-17, release date: 2024-07-03, Last modification date: 2024-10-09)

Primary citation

Yan, R.,Chen, H.,Liu, C.,Zhao, J.,Wu, D.,Jiang, J.,Gong, J.,Jiang, D.
Human XPR1 structures reveal phosphate export mechanism.
Nature, 633:960-967, 2024

PubMed Abstract: Inorganic phosphate (Pi) is a fundamental macronutrient for all living organisms, the homeostasis of which is critical for numerous biological activities. As the only known human Pi exporter to date, XPR1 has an indispensable role in cellular Pi homeostasis. Dysfunction of XPR1 is associated with neurodegenerative disease. However, the mechanisms underpinning XPR1-mediated Pi efflux and regulation by the intracellular inositol polyphosphate (InsPP) sensor SPX domain remain poorly understood. Here we present cryo-electron microscopy structures of human XPR1 in Pi-bound closed, open and InsP-bound forms, revealing the structural basis for XPR1 gating and regulation by InsPPs. XPR1 consists of an N-terminal SPX domain, a dimer-formation core domain and a Pi transport domain. Within the transport domain, three basic clusters are responsible for Pi binding and transport, and a conserved W573 acts as a molecular switch for gating. In addition, the SPX domain binds to InsP and facilitates Pi efflux by liberating the C-terminal loop that limits Pi entry. This study provides a conceptual framework for the mechanistic understanding of Pi homeostasis by XPR1 homologues in fungi, plants and animals.

PubMed: 39169184
DOI: 10.1038/s41586-024-07852-9

Experimental method

ELECTRON MICROSCOPY (2.96 Å)