+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-40339 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Title | Human OCT1 bound to thiamine in inward-open conformation | |||||||||
Map data | Human OCT1 bound to thiamine in inward-open conformation | |||||||||
Sample |
| |||||||||
Keywords | membrane protein / MFS / drug transporter / TRANSPORT PROTEIN | |||||||||
Function / homology | Function and homology information secondary active organic cation transmembrane transporter activity / putrescine transmembrane transporter activity / (R)-carnitine transmembrane transporter activity / acyl carnitine transmembrane transport / pyrimidine nucleoside transmembrane transporter activity / acetylcholine transmembrane transporter activity / acetylcholine transport / serotonin transport / spermidine transmembrane transporter activity / quaternary ammonium group transmembrane transporter activity ...secondary active organic cation transmembrane transporter activity / putrescine transmembrane transporter activity / (R)-carnitine transmembrane transporter activity / acyl carnitine transmembrane transport / pyrimidine nucleoside transmembrane transporter activity / acetylcholine transmembrane transporter activity / acetylcholine transport / serotonin transport / spermidine transmembrane transporter activity / quaternary ammonium group transmembrane transporter activity / organic cation transport / quaternary ammonium group transport / epinephrine transport / thiamine transmembrane transport / purine-containing compound transmembrane transport / spermidine transport / thiamine transmembrane transporter activity / Organic cation transport / organic cation transmembrane transporter activity / putrescine transport / thiamine transport / dopamine uptake / metanephric proximal tubule development / prostaglandin transport / norepinephrine:sodium symporter activity / prostaglandin transmembrane transporter activity / toxin transmembrane transporter activity / Abacavir transmembrane transport / Norepinephrine Neurotransmitter Release Cycle / dopamine:sodium symporter activity / norepinephrine transport / serotonin uptake / neurotransmitter transmembrane transporter activity / dopamine transport / establishment or maintenance of transmembrane electrochemical gradient / organic anion transmembrane transporter activity / xenobiotic transport across blood-brain barrier / monoamine transmembrane transporter activity / Neurotransmitter clearance / Na+/Cl- dependent neurotransmitter transporters / monoamine transport / Ciprofloxacin ADME / xenobiotic transport / cellular detoxification / neurotransmitter transport / xenobiotic transmembrane transporter activity / transport across blood-brain barrier / lateral plasma membrane / basal plasma membrane / xenobiotic metabolic process / presynapse / basolateral plasma membrane / apical plasma membrane / identical protein binding / membrane / plasma membrane Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.13 Å | |||||||||
Authors | Zeng YC / Sobti M / Stewart AG | |||||||||
Funding support | Australia, 1 items
| |||||||||
Citation | Journal: Nat Commun / Year: 2023 Title: Structural basis of promiscuous substrate transport by Organic Cation Transporter 1. Authors: Yi C Zeng / Meghna Sobti / Ada Quinn / Nicola J Smith / Simon H J Brown / Jamie I Vandenberg / Renae M Ryan / Megan L O'Mara / Alastair G Stewart / Abstract: Organic Cation Transporter 1 (OCT1) plays a crucial role in hepatic metabolism by mediating the uptake of a range of metabolites and drugs. Genetic variations can alter the efficacy and safety of ...Organic Cation Transporter 1 (OCT1) plays a crucial role in hepatic metabolism by mediating the uptake of a range of metabolites and drugs. Genetic variations can alter the efficacy and safety of compounds transported by OCT1, such as those used for cardiovascular, oncological, and psychological indications. Despite its importance in drug pharmacokinetics, the substrate selectivity and underlying structural mechanisms of OCT1 remain poorly understood. Here, we present cryo-EM structures of full-length human OCT1 in the inward-open conformation, both ligand-free and drug-bound, indicating the basis for its broad substrate recognition. Comparison of our structures with those of outward-open OCTs provides molecular insight into the alternating access mechanism of OCTs. We observe that hydrophobic gates stabilize the inward-facing conformation, whereas charge neutralization in the binding pocket facilitates the release of cationic substrates. These findings provide a framework for understanding the structural basis of the promiscuity of drug binding and substrate translocation in OCT1. | |||||||||
History |
|
-Structure visualization
Supplemental images |
---|
-Downloads & links
-EMDB archive
Map data | emd_40339.map.gz | 59.7 MB | EMDB map data format | |
---|---|---|---|---|
Header (meta data) | emd-40339-v30.xml emd-40339.xml | 14.2 KB 14.2 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_40339_fsc.xml | 8.4 KB | Display | FSC data file |
Images | emd_40339.png | 90.5 KB | ||
Filedesc metadata | emd-40339.cif.gz | 5.7 KB | ||
Others | emd_40339_half_map_1.map.gz emd_40339_half_map_2.map.gz | 59.4 MB 59.4 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-40339 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-40339 | HTTPS FTP |
-Validation report
Summary document | emd_40339_validation.pdf.gz | 754.5 KB | Display | EMDB validaton report |
---|---|---|---|---|
Full document | emd_40339_full_validation.pdf.gz | 754 KB | Display | |
Data in XML | emd_40339_validation.xml.gz | 16.2 KB | Display | |
Data in CIF | emd_40339_validation.cif.gz | 20.9 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-40339 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-40339 | HTTPS FTP |
-Related structure data
Related structure data | 8sc6MC 8sc1C 8sc2C 8sc3C 8sc4C M: atomic model generated by this map C: citing same article (ref.) |
---|---|
Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
---|---|
Related items in Molecule of the Month |
-Map
File | Download / File: emd_40339.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | Human OCT1 bound to thiamine in inward-open conformation | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.84 Å | ||||||||||||||||||||
Density |
| ||||||||||||||||||||
Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
|
-Supplemental data
-Half map: Half Map 1
File | emd_40339_half_map_1.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | Half Map 1 | ||||||||||||
Projections & Slices |
| ||||||||||||
Density Histograms |
-Half map: Half Map 2
File | emd_40339_half_map_2.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | Half Map 2 | ||||||||||||
Projections & Slices |
| ||||||||||||
Density Histograms |
-Sample components
-Entire : Human OCT1
Entire | Name: Human OCT1 |
---|---|
Components |
|
-Supramolecule #1: Human OCT1
Supramolecule | Name: Human OCT1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
---|---|
Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Solute carrier family 22 member 1
Macromolecule | Name: Solute carrier family 22 member 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
---|---|
Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 61.200664 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MPTVDDILEQ VGESGWFQKQ AFLILCLLSA AFAPICVGIV FLGFTPDHHC QSPGVAELSQ RCGWSPAEEL NYTVPGLGPA GEAFLGQCR RYEVDWNQSA LSCVDPLASL ATNRSHLPLG PCQDGWVYDT PGSSIVTEFN LVCADSWKLD LFQSCLNAGF L FGSLGVGY ...String: MPTVDDILEQ VGESGWFQKQ AFLILCLLSA AFAPICVGIV FLGFTPDHHC QSPGVAELSQ RCGWSPAEEL NYTVPGLGPA GEAFLGQCR RYEVDWNQSA LSCVDPLASL ATNRSHLPLG PCQDGWVYDT PGSSIVTEFN LVCADSWKLD LFQSCLNAGF L FGSLGVGY FADRFGRKLC LLGTVLVNAV SGVLMAFSPN YMSMLLFRLL QGLVSKGNWM AGYTLITEFV GSGSRRTVAI MY QMAFTVG LVALTGLAYA LPHWRWLQLA VSLPTFLFLL YYWCVPESPR WLLSQKRNTE AIKIMDHIAQ KNGKLPPADL KML SLEEDV TEKLSPSFAD LFRTPRLRKR TFILMYLWFT DSVLYQGLIL HMGATSGNLY LDFLYSALVE IPGAFIALIT IDRV GRIYP MAMSNLLAGA ACLVMIFISP DLHWLNIIIM CVGRMGITIA IQMICLVNAE LYPTFVRNLG VMVCSSLCDI GGIIT PFIV FRLREVWQAL PLILFAVLGL LAAGVTLLLP ETKGVALPET MKDAENLGRK AKPKENTIYL KVQTSEPSGT UniProtKB: Solute carrier family 22 member 1 |
-Macromolecule #2: 3-(4-AMINO-2-METHYL-PYRIMIDIN-5-YLMETHYL)-5-(2-HYDROXY-ETHYL)-4-M...
Macromolecule | Name: 3-(4-AMINO-2-METHYL-PYRIMIDIN-5-YLMETHYL)-5-(2-HYDROXY-ETHYL)-4-METHYL-THIAZOL-3-IUM type: ligand / ID: 2 / Number of copies: 1 / Formula: VIB |
---|---|
Molecular weight | Theoretical: 265.355 Da |
Chemical component information | ChemComp-VIB: |
-Experimental details
-Structure determination
Method | cryo EM |
---|---|
Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 8 |
---|---|
Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
---|---|
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 88.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.5 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |