Inorganic phosphate (P) is a fundamental and essential element for nucleotide biosynthesis, energy supply, and cellular signaling in living organisms. Human phosphate transporter (PiT) dysfunction causes numerous diseases, but the molecular mechanism underlying transporters remains elusive. We report the structure of the sodium-dependent phosphate transporter from (PiT) in complex with sodium and phosphate (PiT-Na/Pi) at 2.3-angstrom resolution. We reveal that one phosphate and two sodium ions (Pi-2Na) are located at the core of PiT and that the third sodium ion (Na) is located near the inner membrane boundary. We propose an elevator-like mechanism for sodium and phosphate transport by PiT, with the PiT-Na/Pi complex adopting an inward occluded conformation. We found that disease-related PiT variants carry mutations in the corresponding sodium- and phosphate-binding residues identified in PiT. Our three-dimensional structure of PiT provides a framework for understanding PiT dysfunction and for future structure-based drug design.
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| http://dx.doi.org/10.1126/sciadv.abb4024 | DOI Listing |
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