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- PDB-7dsq: Overall structure of the LAT1-4F2hc bound with 3,5-diiodo-L-tyrosine -
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Open data
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Basic information
Entry | Database: PDB / ID: 7dsq | ||||||||||||
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Title | Overall structure of the LAT1-4F2hc bound with 3,5-diiodo-L-tyrosine | ||||||||||||
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![]() | MEMBRANE PROTEIN / LAT1-4F2hc | ||||||||||||
Function / homology | ![]() L-tryptophan transmembrane transporter activity / alanine transport / L-tryptophan transmembrane transport / positive regulation of L-leucine import across plasma membrane / cellular response to L-arginine / thyroid hormone transmembrane transporter activity / neutral L-amino acid secondary active transmembrane transporter activity / amino acid import across plasma membrane / Defective SLC7A7 causes lysinuric protein intolerance (LPI) / methionine transport ...L-tryptophan transmembrane transporter activity / alanine transport / L-tryptophan transmembrane transport / positive regulation of L-leucine import across plasma membrane / cellular response to L-arginine / thyroid hormone transmembrane transporter activity / neutral L-amino acid secondary active transmembrane transporter activity / amino acid import across plasma membrane / Defective SLC7A7 causes lysinuric protein intolerance (LPI) / methionine transport / tyrosine transport / L-histidine transport / apical pole of neuron / aromatic amino acid transmembrane transporter activity / amino acid transport complex / L-leucine import across plasma membrane / L-alanine transmembrane transporter activity / isoleucine transport / L-alanine import across plasma membrane / L-amino acid transmembrane transporter activity / phenylalanine transport / valine transport / amino acid transmembrane transport / L-leucine transmembrane transporter activity / calcium:sodium antiporter activity / L-leucine transport / thyroid hormone transport / proline transport / positive regulation of cytokine production involved in immune response / negative regulation of vascular associated smooth muscle cell apoptotic process / neutral amino acid transport / amino acid transmembrane transporter activity / external side of apical plasma membrane / Amino acid transport across the plasma membrane / neutral L-amino acid transmembrane transporter activity / Tryptophan catabolism / exogenous protein binding / xenobiotic transport / anchoring junction / response to muscle activity / antiporter activity / Basigin interactions / microvillus membrane / amino acid transport / positive regulation of interleukin-4 production / response to exogenous dsRNA / positive regulation of interleukin-17 production / positive regulation of glial cell proliferation / tryptophan transport / transport across blood-brain barrier / response to hyperoxia / cellular response to glucose starvation / basal plasma membrane / liver regeneration / negative regulation of autophagy / positive regulation of type II interferon production / peptide antigen binding / calcium ion transport / double-stranded RNA binding / virus receptor activity / melanosome / basolateral plasma membrane / cellular response to lipopolysaccharide / carbohydrate metabolic process / cadherin binding / apical plasma membrane / symbiont entry into host cell / protein heterodimerization activity / lysosomal membrane / negative regulation of gene expression / intracellular membrane-bounded organelle / synapse / cell surface / protein homodimerization activity / RNA binding / extracellular exosome / nucleoplasm / membrane / plasma membrane / cytosol Similarity search - Function | ||||||||||||
Biological species | ![]() | ||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å | ||||||||||||
![]() | Yan, R.H. / Li, Y.N. / Zhang, Y.Y. / Zhong, X.Y. / Zhou, Q. | ||||||||||||
Funding support | ![]()
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![]() | ![]() Title: Mechanism of substrate transport and inhibition of the human LAT1-4F2hc amino acid transporter. Authors: Renhong Yan / Yaning Li / Jennifer Müller / Yuanyuan Zhang / Simon Singer / Lu Xia / Xinyue Zhong / Jürg Gertsch / Karl-Heinz Altmann / Qiang Zhou / ![]() ![]() Abstract: LAT1 (SLC7A5) is one of the representative light chain proteins of heteromeric amino acid transporters, forming a heterodimer with its heavy chain partner 4F2hc (SLC3A2). LAT1 is overexpressed in ...LAT1 (SLC7A5) is one of the representative light chain proteins of heteromeric amino acid transporters, forming a heterodimer with its heavy chain partner 4F2hc (SLC3A2). LAT1 is overexpressed in many types of tumors and mediates the transfer of drugs and hormones across the blood-brain barrier. Thus, LAT1 is considered as a drug target for cancer treatment and may be exploited for drug delivery into the brain. Here, we synthesized three potent inhibitors of human LAT1, which inhibit transport of leucine with IC values between 100 and 250 nM, and solved the cryo-EM structures of the corresponding LAT1-4F2hc complexes with these inhibitors bound at resolution of up to 2.7 or 2.8 Å. The protein assumes an outward-facing occluded conformation, with the inhibitors bound in the classical substrate binding pocket, but with their tails wedged between the substrate binding site and TM10 of LAT1. We also solved the complex structure of LAT1-4F2hc with 3,5-diiodo-L-tyrosine (Diiodo-Tyr) at 3.4 Å overall resolution, which revealed a different inhibition mechanism and might represent an intermediate conformation between the outward-facing occluded state mentioned above and the outward-open state. To our knowledge, this is the first time that the outward-facing conformation is revealed for the HAT family. Our results unveil more important insights into the working mechanisms of HATs and provide a structural basis for future drug design. | ||||||||||||
History |
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Structure visualization
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Structure viewer | Molecule: ![]() ![]() |
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PDBx/mmCIF format | ![]() | 180.3 KB | Display | ![]() |
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PDB format | ![]() | 141.1 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Summary document | ![]() | 1.3 MB | Display | ![]() |
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Full document | ![]() | 1.3 MB | Display | |
Data in XML | ![]() | 34 KB | Display | |
Data in CIF | ![]() | 49.8 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 30841MC ![]() 7dskC ![]() 7dslC ![]() 7dsnC M: map data used to model this data C: citing same article ( |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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Components
-Protein , 2 types, 2 molecules AB
#1: Protein | Mass: 70160.828 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
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#2: Protein | Mass: 57186.895 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
-Sugars , 1 types, 4 molecules
#3: Polysaccharide | 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose Source method: isolated from a genetically manipulated source |
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-Non-polymers , 4 types, 19 molecules ![](data/chem/img/TYI.gif)
![](data/chem/img/Y01.gif)
![](data/chem/img/3PH.gif)
![](data/chem/img/HOH.gif)
![](data/chem/img/Y01.gif)
![](data/chem/img/3PH.gif)
![](data/chem/img/HOH.gif)
#4: Chemical | ChemComp-TYI / | ||||
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#5: Chemical | #6: Chemical | ChemComp-3PH / | #7: Water | ChemComp-HOH / | |
-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: LAT1-4F2hc bound with 3,5-diiodo-L-tyrosine / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT |
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Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() |
Buffer solution | pH: 8 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Alignment procedure: COMA FREE |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
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Processing
EM software | Name: RELION / Version: 3.0.6 / Category: 3D reconstruction |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
3D reconstruction | Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 93151 / Symmetry type: POINT |