+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-36651 | |||||||||
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Title | hOCT1 in complex with metformin in outward open conformation | |||||||||
Map data | ||||||||||
Sample |
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Keywords | SLC / transporter / MEMBRANE 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: 4.14 Å | |||||||||
Authors | Zhang S / Zhu A / Kong F / Chen J / Lan B / He G / Gao K / Cheng L / Yan C / Chen L / Liu X | |||||||||
Funding support | China, 1 items
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Citation | Journal: Cell Discov / Year: 2024 Title: Structural insights into human organic cation transporter 1 transport and inhibition. Authors: Shuhao Zhang / Angqi Zhu / Fang Kong / Jianan Chen / Baoliang Lan / Guodong He / Kaixuan Gao / Lili Cheng / Xiaoou Sun / Chuangye Yan / Ligong Chen / Xiangyu Liu / Abstract: The human organic cation transporter 1 (hOCT1), also known as SLC22A1, is integral to hepatic uptake of structurally diversified endogenous and exogenous organic cations, influencing both metabolism ...The human organic cation transporter 1 (hOCT1), also known as SLC22A1, is integral to hepatic uptake of structurally diversified endogenous and exogenous organic cations, influencing both metabolism and drug pharmacokinetics. hOCT1 has been implicated in the therapeutic dynamics of many drugs, making interactions with hOCT1 a key consideration in novel drug development and drug-drug interactions. Notably, metformin, the frontline medication for type 2 diabetes, is a prominent hOCT1 substrate. Conversely, hOCT1 can be inhibited by agents such as spironolactone, a steroid analog inhibitor of the aldosterone receptor, necessitating a deep understanding of hOCT1-drug interactions in the development of new pharmacological treatments. Despite extensive study, specifics of hOCT1 transport and inhibition mechanisms remain elusive at the molecular level. Here, we present cryo-electron microscopy structures of the hOCT1-metformin complex in three distinct conformational states - outward open, outward occluded, and inward occluded as well as substrate-free hOCT1 in both partially and fully open states. We also present hOCT1 in complex with spironolactone in both outward and inward facing conformations. These structures provide atomic-level insights into the dynamic metformin transfer process via hOCT1 and the mechanism by which spironolactone inhibits it. Additionally, we identify a 'YER' motif critical for the conformational flexibility of hOCT1 and likely other SLC22 family transporters. Our findings significantly advance the understanding of hOCT1 molecular function and offer a foundational framework for the design of new therapeutic agents targeting this transporter. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_36651.map.gz | 28.7 MB | EMDB map data format | |
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Header (meta data) | emd-36651-v30.xml emd-36651.xml | 14.4 KB 14.4 KB | Display Display | EMDB header |
Images | emd_36651.png | 34.6 KB | ||
Filedesc metadata | emd-36651.cif.gz | 5.5 KB | ||
Others | emd_36651_half_map_1.map.gz emd_36651_half_map_2.map.gz | 28.3 MB 28.3 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-36651 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-36651 | HTTPS FTP |
-Validation report
Summary document | emd_36651_validation.pdf.gz | 684.1 KB | Display | EMDB validaton report |
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Full document | emd_36651_full_validation.pdf.gz | 683.7 KB | Display | |
Data in XML | emd_36651_validation.xml.gz | 10.7 KB | Display | |
Data in CIF | emd_36651_validation.cif.gz | 12.5 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-36651 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-36651 | HTTPS FTP |
-Related structure data
Related structure data | 8jtsMC 8jttC 8jtvC 8jtwC 8jtxC 8jtyC 8jtzC 8ju0C M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_36651.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 1.0825 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_36651_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_36651_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : human organic cation transporter in compelx wtih metformin in out...
Entire | Name: human organic cation transporter in compelx wtih metformin in outward open conformation |
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Components |
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-Supramolecule #1: human organic cation transporter in compelx wtih metformin in out...
Supramolecule | Name: human organic cation transporter in compelx wtih metformin in outward open conformation type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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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 / Details: metformin / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 62.569164 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
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 EDQVDP RLI DGK UniProtKB: Solute carrier family 22 member 1 |
-Macromolecule #2: Metformin
Macromolecule | Name: Metformin / type: ligand / ID: 2 / Number of copies: 1 / Formula: MF8 |
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Molecular weight | Theoretical: 129.164 Da |
Chemical component information | ChemComp-MF8: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 8 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 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: 1.5 µm / Nominal defocus min: 1.1 µm |
-Image processing
Startup model | Type of model: NONE |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 4.14 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 342359 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |