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- PDB-9kxy: Structure of human B0AT1-ACE2 complex with compound1 -

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Basic information

Entry
Database: PDB / ID: 9kxy
TitleStructure of human B0AT1-ACE2 complex with compound1
Components
  • Angiotensin-converting enzyme 2
  • Sodium-dependent neutral amino acid transporter B(0)AT1
KeywordsTRANSPORT PROTEIN / Inhibitor / amino acid transporter / SLC6
Function / homology
Function and homology information


alanine:sodium symporter activity / Defective transport of neurotransmitters by SLC6A19 causes Hartnup disorder (HND) / Defective transport of amino acids by SLC6A19 causes Hartnup disorder (HND) / glycine:sodium symporter activity / neutral amino acid transport / neutral L-amino acid transmembrane transporter activity / SLC-mediated transport of neurotransmitters / Amino acid transport across the plasma membrane / amino acid transmembrane transporter activity / positive regulation of amino acid transport ...alanine:sodium symporter activity / Defective transport of neurotransmitters by SLC6A19 causes Hartnup disorder (HND) / Defective transport of amino acids by SLC6A19 causes Hartnup disorder (HND) / glycine:sodium symporter activity / neutral amino acid transport / neutral L-amino acid transmembrane transporter activity / SLC-mediated transport of neurotransmitters / Amino acid transport across the plasma membrane / amino acid transmembrane transporter activity / positive regulation of amino acid transport / angiotensin-converting enzyme 2 / positive regulation of L-proline import across plasma membrane / Hydrolases; Acting on peptide bonds (peptidases); Metallocarboxypeptidases / neurotransmitter transport / angiotensin-mediated drinking behavior / amino acid transport / positive regulation of gap junction assembly / tryptophan transport / regulation of systemic arterial blood pressure by renin-angiotensin / maternal process involved in female pregnancy / regulation of cardiac conduction / carboxypeptidase activity / transporter activator activity / peptidyl-dipeptidase activity / amino acid import across plasma membrane / regulation of vasoconstriction / Metabolism of Angiotensinogen to Angiotensins / receptor-mediated endocytosis of virus by host cell / angiotensin maturation / viral life cycle / transmembrane transporter complex / Attachment and Entry / metallocarboxypeptidase activity / positive regulation of cardiac muscle contraction / regulation of cytokine production / response to nutrient / blood vessel diameter maintenance / negative regulation of smooth muscle cell proliferation / brush border membrane / sodium ion transmembrane transport / negative regulation of ERK1 and ERK2 cascade / virus receptor activity / positive regulation of reactive oxygen species metabolic process / metallopeptidase activity / endocytic vesicle membrane / cilium / regulation of cell population proliferation / regulation of inflammatory response / endopeptidase activity / Induction of Cell-Cell Fusion / Potential therapeutics for SARS / membrane fusion / Attachment and Entry / entry receptor-mediated virion attachment to host cell / receptor-mediated virion attachment to host cell / apical plasma membrane / membrane raft / endoplasmic reticulum lumen / symbiont entry into host cell / negative regulation of transcription by RNA polymerase II / cell surface / extracellular exosome / zinc ion binding / extracellular region / membrane / identical protein binding / plasma membrane / cytoplasm
Similarity search - Function
Neutral amino acid SLC6 transporter / Sodium:neurotransmitter symporter family signature 1. / Sodium:neurotransmitter symporter / Sodium:neurotransmitter symporter superfamily / Sodium:neurotransmitter symporter family / Sodium:neurotransmitter symporter family profile. / Collectrin domain / Renal amino acid transporter / Collectrin-like domain profile. / Peptidase M2, peptidyl-dipeptidase A ...Neutral amino acid SLC6 transporter / Sodium:neurotransmitter symporter family signature 1. / Sodium:neurotransmitter symporter / Sodium:neurotransmitter symporter superfamily / Sodium:neurotransmitter symporter family / Sodium:neurotransmitter symporter family profile. / Collectrin domain / Renal amino acid transporter / Collectrin-like domain profile. / Peptidase M2, peptidyl-dipeptidase A / Angiotensin-converting enzyme / Peptidase family M2 domain profile. / Neutral zinc metallopeptidases, zinc-binding region signature.
Similarity search - Domain/homology
: / Sodium-dependent neutral amino acid transporter B(0)AT1 / Angiotensin-converting enzyme 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.82 Å
AuthorsImazu, T. / Miyaguchi, I.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Commun Biol / Year: 2026
Title: Structure-guided development of a potent human BAT1 inhibitor effective in a mouse model of phenylketonuria.
Authors: Takuya Imazu / Tomoya Akashi / Masahiro Hiraizumi / Yosuke Inui / Wataru Sasaki / Tsuyoshi Takahashi / Hidenori Todoroki / Taichi Kumanomidou / Kazunori Yamada / Norie Fujikawa / Hiromi ...Authors: Takuya Imazu / Tomoya Akashi / Masahiro Hiraizumi / Yosuke Inui / Wataru Sasaki / Tsuyoshi Takahashi / Hidenori Todoroki / Taichi Kumanomidou / Kazunori Yamada / Norie Fujikawa / Hiromi Hisano / Hidetsugu Asada / Tsukasa Kusakizako / Tomohiro Nishizawa / So Iwata / Osamu Nureki / Ikuko Miyaguchi /
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 ...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.
History
DepositionDec 7, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 10, 2025Provider: repository / Type: Initial release
Revision 1.0Dec 10, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Dec 10, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Dec 10, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Dec 10, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Dec 10, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Sep 2, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.1Sep 2, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Sodium-dependent neutral amino acid transporter B(0)AT1
B: Angiotensin-converting enzyme 2
C: Sodium-dependent neutral amino acid transporter B(0)AT1
D: Angiotensin-converting enzyme 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)337,61218
Polymers332,0074
Non-polymers5,60514
Water181
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
22
/ NCS ensembles :
ID
1
2

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Components

#1: Protein Sodium-dependent neutral amino acid transporter B(0)AT1 / Solute carrier family 6 member 19 / System B(0) neutral amino acid transporter AT1


Mass: 73289.359 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC6A19, B0AT1 / Production host: Homo sapiens (human) / References: UniProt: Q695T7
#2: Protein Angiotensin-converting enzyme 2 / Angiotensin-converting enzyme homolog / ACEH / Angiotensin-converting enzyme-related ...Angiotensin-converting enzyme homolog / ACEH / Angiotensin-converting enzyme-related carboxypeptidase / ACE-related carboxypeptidase / Metalloprotease MPROT15


Mass: 92713.898 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ACE2, UNQ868/PRO1885 / Production host: Homo sapiens (human)
References: UniProt: Q9BYF1, angiotensin-converting enzyme 2, Hydrolases; Acting on peptide bonds (peptidases); Metallocarboxypeptidases
#3: Polysaccharide
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 12 / Source method: isolated from a natural source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#4: Chemical ChemComp-A1L6U / 3-(3-bromophenyl)-~{N}-ethyl-propanamide


Mass: 256.139 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H14BrNO / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Ternary comple of B0AT1, ACE2 and inhibitor / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1600 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 7.6 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: REFMAC / Version: 5.8.0267 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.82 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 193206 / Symmetry type: POINT
RefinementResolution: 2.82→2.82 Å / Cor.coef. Fo:Fc: 0.889 / SU B: 10.739 / SU ML: 0.205 / ESU R: 0.226
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.3811 --
obs0.3811 472428 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 123.704 Å2
Refinement stepCycle: 1 / Total: 21725
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.010.01322340
ELECTRON MICROSCOPYr_bond_other_d0.0290.01720721
ELECTRON MICROSCOPYr_angle_refined_deg1.6041.65330394
ELECTRON MICROSCOPYr_angle_other_deg1.6191.58847667
ELECTRON MICROSCOPYr_dihedral_angle_1_deg4.72152644
ELECTRON MICROSCOPYr_dihedral_angle_2_deg36.5123.0581112
ELECTRON MICROSCOPYr_dihedral_angle_3_deg15.16153610
ELECTRON MICROSCOPYr_dihedral_angle_4_deg18.331592
ELECTRON MICROSCOPYr_chiral_restr0.0790.22894
ELECTRON MICROSCOPYr_gen_planes_refined0.0050.0225020
ELECTRON MICROSCOPYr_gen_planes_other0.0030.025341
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it8.64312.21910604
ELECTRON MICROSCOPYr_mcbond_other8.63812.21810603
ELECTRON MICROSCOPYr_mcangle_it13.54418.35113238
ELECTRON MICROSCOPYr_mcangle_other13.54518.35313239
ELECTRON MICROSCOPYr_scbond_it10.38613.85611736
ELECTRON MICROSCOPYr_scbond_other10.38613.85711737
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other16.49120.29817157
ELECTRON MICROSCOPYr_long_range_B_refined32.091101617
ELECTRON MICROSCOPYr_long_range_B_other32.091101618
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: ELECTRON MICROSCOPY / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A380160.16
12C380160.16
21B508500.18
22D508500.18
LS refinement shellResolution: 2.5→2.565 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.774 34863 -
obs--100 %

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