+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-32540 | ||||||||||||
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Title | Cryo-EM structure of human TPH2 tetramer | ||||||||||||
Map data | half map 2 | ||||||||||||
Sample |
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Keywords | Human / Tryptophan 5-hydroxylase 2 / tetramer / BIOSYNTHETIC PROTEIN | ||||||||||||
Function / homology | Function and homology information tryptophan 5-monooxygenase / tryptophan 5-monooxygenase activity / Serotonin and melatonin biosynthesis / aromatic amino acid metabolic process / serotonin biosynthetic process / neuron projection / iron ion binding / cytosol Similarity search - Function | ||||||||||||
Biological species | Homo sapiens (human) | ||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.09 Å | ||||||||||||
Authors | Zhu KF / Liu C / Zhang HW / Wang DP | ||||||||||||
Funding support | China, 3 items
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Citation | Journal: Front Pharmacol / Year: 2022 Title: Cryo-EM Structure and Activator Screening of Human Tryptophan Hydroxylase 2. Authors: Kongfu Zhu / Chao Liu / Yuanzhu Gao / Jianping Lu / Daping Wang / Huawei Zhang / Abstract: Human tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in the synthesis of serotonin. Its dysfunction has been implicated in various psychiatric disorders such as depression, autism, and ...Human tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in the synthesis of serotonin. Its dysfunction has been implicated in various psychiatric disorders such as depression, autism, and bipolar disorder. TPH2 is typically decreased in stability and catalytic activity in patients; thus, screening of molecules capable of binding and stabilizing the structure of TPH2 in activated conformation is desired for drug development in mental disorder treatment. Here, we solved the 3.0 Å cryo-EM structure of the TPH2 tetramer. Then, based on the structure, we conducted allosteric site prediction and small-molecule activator screening to the obtained cavity. ZINC000068568685 was successfully selected as the best candidate with highest binding affinity. To better understand the driving forces and binding stability of the complex, we performed molecular dynamics simulation, which indicates that ZINC000068568685 has great potential to stabilize the folding of the TPH2 tetramer to facilitate its activity. The research might shed light on the development of novel drugs targeting TPH2 for the treatment of psychological disorders. | ||||||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_32540.map.gz | 59.8 MB | EMDB map data format | |
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Header (meta data) | emd-32540-v30.xml emd-32540.xml | 14.7 KB 14.7 KB | Display Display | EMDB header |
Images | emd_32540.png | 135.9 KB | ||
Filedesc metadata | emd-32540.cif.gz | 5.4 KB | ||
Others | emd_32540_half_map_1.map.gz emd_32540_half_map_2.map.gz | 12.1 MB 12.1 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-32540 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-32540 | HTTPS FTP |
-Validation report
Summary document | emd_32540_validation.pdf.gz | 678.3 KB | Display | EMDB validaton report |
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Full document | emd_32540_full_validation.pdf.gz | 677.9 KB | Display | |
Data in XML | emd_32540_validation.xml.gz | 12.5 KB | Display | |
Data in CIF | emd_32540_validation.cif.gz | 13.9 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-32540 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-32540 | HTTPS FTP |
-Related structure data
Related structure data | 7wiyMC 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_32540.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Annotation | half map 2 | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.842 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: half map 1
File | emd_32540_half_map_1.map | ||||||||||||
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Annotation | half map 1 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: half map 1
File | emd_32540_half_map_2.map | ||||||||||||
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Annotation | half map 1 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Complex of human TPH2 with bound Fe2+ and imidazole
Entire | Name: Complex of human TPH2 with bound Fe2+ and imidazole |
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Components |
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-Supramolecule #1: Complex of human TPH2 with bound Fe2+ and imidazole
Supramolecule | Name: Complex of human TPH2 with bound Fe2+ and imidazole / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Tryptophan 5-hydroxylase 2
Macromolecule | Name: Tryptophan 5-hydroxylase 2 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO / EC number: tryptophan 5-monooxygenase |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 56.129609 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: MQPAMMMFSS KYWARRGFSL DSAVPEEHQL LGSSTLNKPN SGKNDDKGNK GSSKREAATE SGKTAVVFSL KNEVGGLVKA LRLFQEKRV NMVHIESRKS RRRSSEVEIF VDCECGKTEF NELIQLLKFQ TTIVTLNPPE NIWTEEEELE DVPWFPRKIS E LDKCSHRV ...String: MQPAMMMFSS KYWARRGFSL DSAVPEEHQL LGSSTLNKPN SGKNDDKGNK GSSKREAATE SGKTAVVFSL KNEVGGLVKA LRLFQEKRV NMVHIESRKS RRRSSEVEIF VDCECGKTEF NELIQLLKFQ TTIVTLNPPE NIWTEEEELE DVPWFPRKIS E LDKCSHRV LMYGSELDAD HPGFKDNVYR QRRKYFVDVA MGYKYGQPIP RVEYTEEETK TWGVVFRELS KLYPTHACRE YL KNFPLLT KYCGYREDNV PQLEDVSMFL KERSGFTVRP VAGYLSPRDF LAGLAYRVFH CTQYIRHGSD PLYTPEPDTC HEL LGHVPL LADPKFAQFS QEIGLASLGA SDEDVQKLAT CYFFTIEFGL CKQEGQLRAY GAGLLSSIGE LKHALSDKAC VKAF DPKTT CLQECLITTF QEAYFVSESF EEAKEKMRDF AKSITRPFSV YFNPYTQSIE ILKDTRSIEN VVQDLRSDLN TVCDA LNKM NQYLGI UniProtKB: Tryptophan 5-hydroxylase 2 |
-Macromolecule #2: FE (III) ION
Macromolecule | Name: FE (III) ION / type: ligand / ID: 2 / Number of copies: 4 / Formula: FE |
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Molecular weight | Theoretical: 55.845 Da |
-Macromolecule #3: IMIDAZOLE
Macromolecule | Name: IMIDAZOLE / type: ligand / ID: 3 / Number of copies: 4 / Formula: IMD |
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Molecular weight | Theoretical: 69.085 Da |
Chemical component information | ChemComp-IMD: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 2.5 mg/mL |
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Buffer | pH: 7.5 |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k 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: 2.5 µm / Nominal defocus min: 1.5 µm |
-Image processing
Startup model | Type of model: PDB ENTRY PDB model - PDB ID: |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.09 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 318441 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |