+Open data
-Basic information
Entry | Database: PDB / ID: 7um4 | |||||||||
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Title | Crystal structure of inactive 5-HT5AR in complex with AS2674723 | |||||||||
Components |
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Keywords | MEMBRANE PROTEIN / GPCR / inactive state / 5-HT5AR / HTR5A | |||||||||
Function / homology | Function and homology information adenylate cyclase-inhibiting serotonin receptor signaling pathway / Serotonin receptors / serotonin binding / G protein-coupled serotonin receptor activity / postsynaptic specialization membrane / neurotransmitter receptor activity / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / hippocampus development / adenylate cyclase-activating G protein-coupled receptor signaling pathway / response to estradiol ...adenylate cyclase-inhibiting serotonin receptor signaling pathway / Serotonin receptors / serotonin binding / G protein-coupled serotonin receptor activity / postsynaptic specialization membrane / neurotransmitter receptor activity / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / hippocampus development / adenylate cyclase-activating G protein-coupled receptor signaling pathway / response to estradiol / G alpha (i) signalling events / chemical synaptic transmission / perikaryon / G protein-coupled receptor signaling pathway / dendrite / plasma membrane Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å | |||||||||
Authors | Zhang, S. / Roth, B.L. | |||||||||
Funding support | United States, 2items
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Citation | Journal: Nat Struct Mol Biol / Year: 2022 Title: Inactive and active state structures template selective tools for the human 5-HT receptor. Authors: Shicheng Zhang / He Chen / Chengwei Zhang / Ying Yang / Petr Popov / Jing Liu / Brian E Krumm / Can Cao / Kuglae Kim / Yan Xiong / Vsevolod Katritch / Brian K Shoichet / Jian Jin / Jonathan ...Authors: Shicheng Zhang / He Chen / Chengwei Zhang / Ying Yang / Petr Popov / Jing Liu / Brian E Krumm / Can Cao / Kuglae Kim / Yan Xiong / Vsevolod Katritch / Brian K Shoichet / Jian Jin / Jonathan F Fay / Bryan L Roth / Abstract: Serotonin receptors are important targets for established therapeutics and drug development as they are expressed throughout the human body and play key roles in cell signaling. There are 12 ...Serotonin receptors are important targets for established therapeutics and drug development as they are expressed throughout the human body and play key roles in cell signaling. There are 12 serotonergic G protein-coupled receptor members encoded in the human genome, of which the 5-hydroxytryptamine (5-HT) receptor (5-HTR) is the least understood and lacks selective tool compounds. Here, we report four high-resolution (2.73-2.80 Å) structures of human 5-HTRs, including an inactive state structure bound to an antagonist AS2674723 by crystallization and active state structures bound to a partial agonist lisuride and two full agonists, 5-carboxamidotryptamine (5-CT) and methylergometrine, by cryo-EM. Leveraging the new structures, we developed a highly selective and potent antagonist for 5-HTR. Collectively, these findings both enhance our understanding of this enigmatic receptor and provide a roadmap for structure-based drug discovery for 5-HTR. | |||||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7um4.cif.gz | 109.1 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7um4.ent.gz | 78.3 KB | Display | PDB format |
PDBx/mmJSON format | 7um4.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/um/7um4 ftp://data.pdbj.org/pub/pdb/validation_reports/um/7um4 | HTTPS FTP |
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-Related structure data
Related structure data | 7um5C 7um6C 7um7C 4iarS 4s0vS S: Starting model for refinement C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
-Protein , 2 types, 2 molecules AB
#1: Protein | Mass: 38004.398 Da / Num. of mol.: 1 / Mutation: D65N, I278A Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: HTR5A / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P47898 |
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#2: Protein | Mass: 22251.660 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm) |
-Non-polymers , 6 types, 15 molecules
#3: Chemical | ChemComp-PGE / | ||||||||
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#4: Chemical | #5: Chemical | ChemComp-PG4 / | #6: Chemical | ChemComp-1PE / | #7: Chemical | ChemComp-NN6 / ~{ | #8: Water | ChemComp-HOH / | |
-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.26 Å3/Da / Density % sol: 45.55 % |
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Crystal grow | Temperature: 293 K / Method: lipidic cubic phase Details: 0.1 M Sodium chloride, 0.1 M Lithium sulfate, 0.1 M DL-Malic acid pH 5.9, 30 % v/v PEG 400 |
-Data collection
Diffraction | Mean temperature: 80 K / Serial crystal experiment: N | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Diffraction source | Source: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.033 Å | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Detector | Type: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Aug 13, 2019 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Radiation wavelength | Wavelength: 1.033 Å / Relative weight: 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reflection | Resolution: 2.8→50 Å / Num. obs: 13732 / % possible obs: 99.2 % / Redundancy: 6.6 % / Biso Wilson estimate: 68.7 Å2 / Rmerge(I) obs: 0.307 / Rpim(I) all: 0.122 / Rrim(I) all: 0.332 / Χ2: 0.897 / Net I/σ(I): 5.8 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reflection shell | Diffraction-ID: 1
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-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 4S0V, 4IAR Resolution: 2.8→44.73 Å / SU ML: 0.46 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 31.13 / Stereochemistry target values: ML
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Solvent computation | Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL | ||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso max: 143.5 Å2 / Biso mean: 67.5536 Å2 / Biso min: 40.18 Å2 | ||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: final / Resolution: 2.8→44.73 Å
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LS refinement shell | Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 5
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