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- EMDB-36922: Cryo-EM structure of human OATP1B1 in complex with DCF -

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Basic information

Entry
Database: EMDB / ID: EMD-36922
TitleCryo-EM structure of human OATP1B1 in complex with DCF
Map data
Sample
  • Complex: OATP1B1
    • Protein or peptide: Solute carrier organic anion transporter family member 1B1
  • Ligand: 2',7'-bis(chloranyl)-3',6'-bis(oxidanyl)spiro[2-benzofuran-3,9'-xanthene]-1-one
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordstransporter / OATP1B1 / organic anion transporting peptide / MEMBRANE PROTEIN
Function / homology
Function and homology information


Defective SLCO1B1 causes hyperbilirubinemia, Rotor type (HBLRR) / Transport of organic anions / sodium-independent organic anion transport / sodium-independent organic anion transmembrane transporter activity / thyroid hormone transmembrane transporter activity / prostaglandin transmembrane transporter activity / Atorvastatin ADME / heme catabolic process / organic anion transport / organic anion transmembrane transporter activity ...Defective SLCO1B1 causes hyperbilirubinemia, Rotor type (HBLRR) / Transport of organic anions / sodium-independent organic anion transport / sodium-independent organic anion transmembrane transporter activity / thyroid hormone transmembrane transporter activity / prostaglandin transmembrane transporter activity / Atorvastatin ADME / heme catabolic process / organic anion transport / organic anion transmembrane transporter activity / bile acid transmembrane transporter activity / bile acid and bile salt transport / Heme degradation / monoatomic ion transport / Recycling of bile acids and salts / xenobiotic metabolic process / basal plasma membrane / basolateral plasma membrane / membrane / plasma membrane
Similarity search - Function
Organic anion transporter polypeptide / Organic Anion Transporter Polypeptide (OATP) family / Kazal-type serine protease inhibitor domain / Kazal domain superfamily / Kazal domain / Kazal domain profile. / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
Solute carrier organic anion transporter family member 1B1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.92 Å
AuthorsShan Z / Yang X / Zhang Y
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Cell Res / Year: 2023
Title: Cryo-EM structures of human organic anion transporting polypeptide OATP1B1.
Authors: Ziyang Shan / Xuemei Yang / Huihui Liu / Yafei Yuan / Yuan Xiao / Jing Nan / Wei Zhang / Wenqi Song / Jufang Wang / Feiwen Wei / Yanqing Zhang /
Abstract: Members of the solute carrier organic anion transporting polypeptide (OATPs) family function as transporters for a large variety of amphipathic organic anions including endogenous metabolites and ...Members of the solute carrier organic anion transporting polypeptide (OATPs) family function as transporters for a large variety of amphipathic organic anions including endogenous metabolites and clinical drugs, such as bile salts, steroids, thyroid hormones, statins, antibiotics, antivirals, and anticancer drugs. OATP1B1 plays a vital role in transporting such substances into the liver for hepatic clearance. FDA and EMA recommend conducting in vitro testing of drug-drug interactions (DDIs) involving OATP1B1. However, the structure and working mechanism of OATPs still remains elusive. In this study, we determined cryo-EM structures of human OATP1B1 bound with representative endogenous metabolites (bilirubin and estrone-3-sulfate), a clinical drug (simeprevir), and a fluorescent indicator (2',7'-dichlorofluorescein), in both outward- and inward-open states. These structures reveal major and minor substrate binding pockets and conformational changes during transport. In combination with mutagenesis studies and molecular dynamics simulations, our work comprehensively elucidates the transport mechanism of OATP1B1 and provides the structural basis for DDI predictions involving OATP1B1, which will greatly promote our understanding of OATPs.
History
DepositionJul 25, 2023-
Header (metadata) releaseSep 13, 2023-
Map releaseSep 13, 2023-
UpdateDec 20, 2023-
Current statusDec 20, 2023Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_36922.png

Downloads & links

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Map

FileDownload / File: emd_36922.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.93 Å/pix.
x 256 pix.
= 238.592 Å		0.93 Å/pix.
x 256 pix.
= 238.592 Å		0.93 Å/pix.
x 256 pix.
= 238.592 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.932 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.25
Minimum - Maximum-2.375533 - 4.186566
Average (Standard dev.)0.00028061788 (±0.092458345)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 238.592 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_36922_msk_1.map
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Half map: #2

Fileemd_36922_half_map_1.map
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Half map: #1

Fileemd_36922_half_map_2.map
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Sample components

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Entire : OATP1B1

EntireName: OATP1B1
Components
  • Complex: OATP1B1
    • Protein or peptide: Solute carrier organic anion transporter family member 1B1
  • Ligand: 2',7'-bis(chloranyl)-3',6'-bis(oxidanyl)spiro[2-benzofuran-3,9'-xanthene]-1-one
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: OATP1B1

SupramoleculeName: OATP1B1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Solute carrier organic anion transporter family member 1B1

MacromoleculeName: Solute carrier organic anion transporter family member 1B1
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 80.330312 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDQNQHLNKT AEAQPSENKK TRYCNGLKMF LAALSLSFIA KTLGAIIMKS SIIHIERRFE ISSSLVGFID GSFEIGNLLV IVFVSYFGS KLHRPKLIGI GCFIMGIGGV LTALPHFFMG YYRYSKETNI NSSENSTSTL STCLINQILS LNRASPEIVG K GCLKESGS ...String:
MDQNQHLNKT AEAQPSENKK TRYCNGLKMF LAALSLSFIA KTLGAIIMKS SIIHIERRFE ISSSLVGFID GSFEIGNLLV IVFVSYFGS KLHRPKLIGI GCFIMGIGGV LTALPHFFMG YYRYSKETNI NSSENSTSTL STCLINQILS LNRASPEIVG K GCLKESGS YMWIYVFMGN MLRGIGETPI VPLGLSYIDD FAKEGHSSLY LGILNAIAMI GPIIGFTLGS LFSKMYVDIG YV DLSTIRI TPTDSRWVGA WWLNFLVSGL FSIISSIPFF FLPQTPNKPQ KERKASLSLH VLETNDEKDQ TANLTNQGKN ITK NVTGFF QSFKSILTNP LYVMFVLLTL LQVSSYIGAF TYVFKYVEQQ YGQPSSKANI LLGVITIPIF ASGMFLGGYI IKKF KLNTV GIAKFSCFTA VMSLSFYLLY FFILCENKSV AGLTMTYDGN NPVTSHRDVP LSYCNSDCNC DESQWEPVCG NNGIT YISP CLAGCKSSSG NKKPIVFYNC SCLEVTGLQN RNYSAHLGEC PRDDACTRKF YFFVAIQVLN LFFSALGGTS HVMLIV KIV QPELKSLALG FHSMVIRALG GILAPIYFGA LIDTTCIKWS TNNCGTRGSC RTYNSTSFSR VYLGLSSMLR VSSLVLY II LIYAMKKKYQ EKDINASENG SVMDEANLES LNKNKHFVPS AGADSETHCL EGSDEVDAGS HHHHHHHHHH GSVEDYKD D DDK

UniProtKB: Solute carrier organic anion transporter family member 1B1

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Macromolecule #3: 2',7'-bis(chloranyl)-3',6'-bis(oxidanyl)spiro[2-benzofuran-3,9'-x...

MacromoleculeName: 2',7'-bis(chloranyl)-3',6'-bis(oxidanyl)spiro[2-benzofuran-3,9'-xanthene]-1-one
type: ligand / ID: 3 / Details: 2',7'-dichlorofluorescein / Number of copies: 1 / Formula: IOQ
Molecular weightTheoretical: 401.196 Da
Chemical component information

ChemComp-IOQ:
2',7'-bis(chloranyl)-3',6'-bis(oxidanyl)spiro[2-benzofuran-3,9'-xanthene]-1-one

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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: 1 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

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

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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

Concentration9 mg/mL
BufferpH: 8
GridMaterial: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 281 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris X / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 46.1 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.9 µm / Nominal magnification: 130000
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: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.92 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 325151
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
FSC plot (resolution estimation)

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