9KXW

Structure of human B0AT1-ACE2

Summary for 9KXW

• Entry DOI: 10.2210/pdb9kxw/pdb
• EMDB information: 62630
• Descriptor: Sodium-dependent neutral amino acid transporter B(0)AT1, Angiotensin-converting enzyme 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: inhibitor, amino acid transporter, slc6, transport protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 166671.86

Authors

Imazu, T.,Miyaguchi, I.,Hiraizumi, M. (deposition date: 2024-12-07, release date: 2025-12-10, Last modification date: 2026-09-02)

Primary citation

Imazu, T.,Akashi, T.,Hiraizumi, M.,Inui, Y.,Sasaki, W.,Takahashi, T.,Todoroki, H.,Kumanomidou, T.,Yamada, K.,Fujikawa, N.,Hisano, H.,Asada, H.,Kusakizako, T.,Nishizawa, T.,Iwata, S.,Nureki, O.,Miyaguchi, I.
Structure-guided development of a potent human B 0 AT1 inhibitor effective in a mouse model of phenylketonuria.
Commun Biol, 2026

PubMed Abstract: BAT1 (SLC6A19) is a neutral amino acid transporter mediating intestinal absorption and renal reuptake of amino acids, including phenylalanine (Phe). Inhibiting BAT1 enhances Phe excretion, offering a therapeutic strategy for phenylketonuria (PKU). Using cryo-EM, we determined human BAT1 structures in outward- and inward-open states, revealing an allosteric pocket ~17 Å from the substrate site that is present in the outward-open conformation and has been previously reported. Structure-guided inhibitor design targeting this pocket produced a potent BAT1 inhibitor that locks the transporter in an outward-occluded state and blocks transport. The higher-resolution structures reveal detailed interactions at the binding site, including water-mediated coordination and conformational changes around Leu52. This inhibitor exhibited submicromolar IC against both human and mouse BAT1, and oral administration in PKU model mice increased urinary Phe and reduced plasma Phe levels. These findings provide structural insight into allosteric inhibition of BAT1 and establish a framework for the rational optimization of inhibitors targeting conformationally dynamic allosteric sites in SLC6-family transporters.

PubMed: 42350764
DOI: 10.1038/s42003-026-10535-y

Experimental method

ELECTRON MICROSCOPY (2.66 Å)