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- EMDB-37428: Cryo-EM structure of ACE2-B0AT1 complex with JX225 -

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Basic information

Entry
Database: EMDB / ID: EMD-37428
TitleCryo-EM structure of ACE2-B0AT1 complex with JX225
Map data
Sample
  • Complex: ACE2-B0AT1 complex with inhibitor JX225
    • Protein or peptide: Sodium-dependent neutral amino acid transporter B(0)AT1
    • Protein or peptide: Angiotensin-converting enzyme 2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 2-(4-bromanyl-3-methyl-phenoxy)-~{N}-propyl-ethanamide
KeywordsTransporter / complex / Inhibitors / PROTEIN TRANSPORT / PROTEIN TRANSPORT-HYDROLASE complex
Function / homology
Function and homology information


Defective SLC6A19 causes Hartnup disorder (HND) / Defective SLC6A19 causes Hartnup disorder (HND) / neutral amino acid transport / amino acid transmembrane transporter activity / Amino acid transport across the plasma membrane / neutral L-amino acid transmembrane transporter activity / symporter activity / Na+/Cl- dependent neurotransmitter transporters / amino acid transport / positive regulation of amino acid transport ...Defective SLC6A19 causes Hartnup disorder (HND) / Defective SLC6A19 causes Hartnup disorder (HND) / neutral amino acid transport / amino acid transmembrane transporter activity / Amino acid transport across the plasma membrane / neutral L-amino acid transmembrane transporter activity / symporter activity / Na+/Cl- dependent neurotransmitter transporters / amino acid transport / 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 / angiotensin-mediated drinking behavior / regulation of systemic arterial blood pressure by renin-angiotensin / positive regulation of gap junction assembly / tryptophan transport / regulation of cardiac conduction / regulation of vasoconstriction / peptidyl-dipeptidase activity / sodium ion transmembrane transport / maternal process involved in female pregnancy / angiotensin maturation / Metabolism of Angiotensinogen to Angiotensins / metallocarboxypeptidase activity / carboxypeptidase activity / negative regulation of signaling receptor activity / Attachment and Entry / positive regulation of cardiac muscle contraction / regulation of cytokine production / viral life cycle / blood vessel diameter maintenance / response to nutrient / brush border membrane / negative regulation of smooth muscle cell proliferation / regulation of transmembrane transporter activity / cilium / negative regulation of ERK1 and ERK2 cascade / metallopeptidase activity / positive regulation of reactive oxygen species metabolic process / endocytic vesicle membrane / regulation of cell population proliferation / virus receptor activity / regulation of inflammatory response / endopeptidase activity / Potential therapeutics for SARS / Induction of Cell-Cell Fusion / entry receptor-mediated virion attachment to host cell / receptor-mediated endocytosis of virus by host cell / membrane fusion / Attachment and Entry / receptor-mediated virion attachment to host cell / symbiont entry into host cell / apical plasma membrane / membrane raft / endoplasmic reticulum lumen / cell surface / extracellular space / extracellular exosome / zinc ion binding / extracellular region / identical protein binding / membrane / plasma membrane
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-like domain profile. / Collectrin domain / Renal amino acid transporter / Peptidase family M2 domain profile. ...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-like domain profile. / Collectrin domain / Renal amino acid transporter / Peptidase family M2 domain profile. / Peptidase M2, peptidyl-dipeptidase A / Angiotensin-converting enzyme / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsYan R / Hu Z / Dai L
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32371267 China
CitationJournal: Nat Commun / Year: 2024
Title: Molecular basis of inhibition of the amino acid transporter BAT1 (SLC6A19).
Authors: Junyang Xu / Ziwei Hu / Lu Dai / Aditya Yadav / Yashan Jiang / Angelika Bröer / Michael G Gardiner / Malcolm McLeod / Renhong Yan / Stefan Bröer /
Abstract: The epithelial neutral amino acid transporter BAT1 (SLC6A19) is the major transporter for the absorption of neutral amino acids in the intestine and their reabsorption in the kidney. Mouse models ...The epithelial neutral amino acid transporter BAT1 (SLC6A19) is the major transporter for the absorption of neutral amino acids in the intestine and their reabsorption in the kidney. Mouse models have demonstrated that lack of BAT1 can normalize elevated plasma amino acids in rare disorders of amino acid metabolism such as phenylketonuria and urea-cycle disorders, implying a pharmacological approach for their treatment. Here we employ a medicinal chemistry approach to generate BAT1 inhibitors with IC-values of 31-90 nM. High-resolution cryo-EM structures of BAT1 in the presence of two compounds from this series identified an allosteric binding site in the vestibule of the transporter. Mechanistically, binding of these inhibitors prevents a movement of TM1 and TM6 that is required for the transporter to make a conformational change from an outward open state to the occluded state.
History
DepositionSep 10, 2023-
Header (metadata) releaseSep 11, 2024-
Map releaseSep 11, 2024-
UpdateSep 11, 2024-
Current statusSep 11, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_37428.png

Downloads & links

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Map

FileDownload / File: emd_37428.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 288 pix.
= 315.36 Å		1.1 Å/pix.
x 288 pix.
= 315.36 Å		1.1 Å/pix.
x 288 pix.
= 315.36 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.095 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.22
Minimum - Maximum-3.131127 - 5.066471
Average (Standard dev.)0.0015835672 (±0.08530832)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 315.36002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_37428_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_37428_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : ACE2-B0AT1 complex with inhibitor JX225

EntireName: ACE2-B0AT1 complex with inhibitor JX225
Components
  • Complex: ACE2-B0AT1 complex with inhibitor JX225
    • Protein or peptide: Sodium-dependent neutral amino acid transporter B(0)AT1
    • Protein or peptide: Angiotensin-converting enzyme 2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 2-(4-bromanyl-3-methyl-phenoxy)-~{N}-propyl-ethanamide

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Supramolecule #1: ACE2-B0AT1 complex with inhibitor JX225

SupramoleculeName: ACE2-B0AT1 complex with inhibitor JX225 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Sodium-dependent neutral amino acid transporter B(0)AT1

MacromoleculeName: Sodium-dependent neutral amino acid transporter B(0)AT1
type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 72.929891 KDa
Recombinant expressionOrganism: Eukaryota (eucaryotes)
SequenceString: DYKDDDDKSG PDEVDASGVR LVLPNPGLDA RIPSLAELET IEQEEASSRP KWDNKAQYML TCLGFCVGLG NVWRFPYLCQ SHGGGAFMI PFLILLVLEG IPLLYLEFAI GQRLRRGSLG VWSSIHPALK GLGLASMLTS FMVGLYYNTI ISWIMWYLFN S FQEPLPWS ...String:
DYKDDDDKSG PDEVDASGVR LVLPNPGLDA RIPSLAELET IEQEEASSRP KWDNKAQYML TCLGFCVGLG NVWRFPYLCQ SHGGGAFMI PFLILLVLEG IPLLYLEFAI GQRLRRGSLG VWSSIHPALK GLGLASMLTS FMVGLYYNTI ISWIMWYLFN S FQEPLPWS DCPLNENQTG YVDECARSSP VDYFWYRETL NISTSISDSG SIQWWMLLCL ACAWSVLYMC TIRGIETTGK AV YITSTLP YVVLTIFLIR GLTLKGATNG IVFLFTPNVT ELAQPDTWLD AGAQVFFSFS LAFGGLISFS SYNSVHNNCE KDS VIVSII NGFTSVYVAI VVYSVIGFRA TQRYDDCFST NILTLINGFD LPEGNVTQEN FVDMQQRCNA SDPAAYAQLV FQTC DINAF LSEAVEGTGL AFIVFTEAIT KMPLSPLWSV LFFIMLFCLG LSSMFGNMEG VVVPLQDLRV IPPKWPKEVL TGLIC LGTF LIGFIFTLNS GQYWLSLLDS YAGSIPLLII AFCEMFSVVY VYGVDRFNKD IEFMIGHKPN IFWQVTWRVV SPLLML IIF LFFFVVEVSQ ELTYSIWDPG YEEFPKSQKI SYPNWVYVVV VIVAGVPSLT IPGYAIYKLI RNHCQKPGDH QGLVSTL ST ASMNGDLKY

UniProtKB: Sodium-dependent neutral amino acid transporter B(0)AT1

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Macromolecule #2: Angiotensin-converting enzyme 2

MacromoleculeName: Angiotensin-converting enzyme 2 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 94.180453 KDa
Recombinant expressionOrganism: Eukaryota (eucaryotes)
SequenceString: MSSSSWLLLS LVAVTAAQST IEEQAKTFLD KFNHEAEDLF YQSSLASWNY NTNITEENVQ NMNNAGDKWS AFLKEQSTLA QMYPLQEIQ NLTVKLQLQA LQQNGSSVLS EDKSKRLNTI LNTMSTIYST GKVCNPDNPQ ECLLLEPGLN EIMANSLDYN E RLWAWESW ...String:
MSSSSWLLLS LVAVTAAQST IEEQAKTFLD KFNHEAEDLF YQSSLASWNY NTNITEENVQ NMNNAGDKWS AFLKEQSTLA QMYPLQEIQ NLTVKLQLQA LQQNGSSVLS EDKSKRLNTI LNTMSTIYST GKVCNPDNPQ ECLLLEPGLN EIMANSLDYN E RLWAWESW RSEVGKQLRP LYEEYVVLKN EMARANHYED YGDYWRGDYE VNGVDGYDYS RGQLIEDVEH TFEEIKPLYE HL HAYVRAK LMNAYPSYIS PIGCLPAHLL GDMWGRFWTN LYSLTVPFGQ KPNIDVTDAM VDQAWDAQRI FKEAEKFFVS VGL PNMTQG FWENSMLTDP GNVQKAVCHP TAWDLGKGDF RILMCTKVTM DDFLTAHHEM GHIQYDMAYA AQPFLLRNGA NEGF HEAVG EIMSLSAATP KHLKSIGLLS PDFQEDNETE INFLLKQALT IVGTLPFTYM LEKWRWMVFK GEIPKDQWMK KWWEM KREI VGVVEPVPHD ETYCDPASLF HVSNDYSFIR YYTRTLYQFQ FQEALCQAAK HEGPLHKCDI SNSTEAGQKL FNMLRL GKS EPWTLALENV VGAKNMNVRP LLNYFEPLFT WLKDQNKNSF VGWSTDWSPY ADQSIKVRIS LKSALGDKAY EWNDNEM YL FRSSVAYAMR QYFLKVKNQM ILFGEEDVRV ANLKPRISFN FFVTAPKNVS DIIPRTEVEK AIRMSRSRIN DAFRLNDN S LEFLGIQPTL GPPNQPPVSI WLIVFGVVMG VIVVGIVILI FTGIRDRKKK NKARSGENPY ASIDISKGEN NPGFQNTDD VQTSFLEHHH HHHHHHH

UniProtKB: Angiotensin-converting enzyme 2

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 6 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #5: 2-(4-bromanyl-3-methyl-phenoxy)-~{N}-propyl-ethanamide

MacromoleculeName: 2-(4-bromanyl-3-methyl-phenoxy)-~{N}-propyl-ethanamide
type: ligand / ID: 5 / Number of copies: 2 / Formula: XF0
Molecular weightTheoretical: 286.165 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Digitization - Dimensions - Width: 5760 pixel / Digitization - Dimensions - Height: 4092 pixel / Number grids imaged: 1 / Number real images: 2211 / Average electron dose: 1.5625 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Calibrated defocus max: 3.0 µm / Calibrated defocus min: 1.5 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 81000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

30040

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1238031
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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