+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-36634 | |||||||||
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Title | 5-HT1A-Gi in complex with compound (R)-IHCH-7179 | |||||||||
Map data | ||||||||||
Sample |
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Keywords | Serotonin receptor / 5-HT1AR / Gi-protein / MEMBRANE PROTEIN | |||||||||
Function / homology | Function and homology information regulation of serotonin secretion / adenylate cyclase-inhibiting serotonin receptor signaling pathway / regulation of hormone secretion / dopamine neurotransmitter receptor activity, coupled via Gs / regulation of behavior / Serotonin receptors / serotonin receptor signaling pathway / receptor-receptor interaction / regulation of dopamine metabolic process / serotonin metabolic process ...regulation of serotonin secretion / adenylate cyclase-inhibiting serotonin receptor signaling pathway / regulation of hormone secretion / dopamine neurotransmitter receptor activity, coupled via Gs / regulation of behavior / Serotonin receptors / serotonin receptor signaling pathway / receptor-receptor interaction / regulation of dopamine metabolic process / serotonin metabolic process / serotonin binding / G protein-coupled serotonin receptor activity / gamma-aminobutyric acid signaling pathway / exploration behavior / neurotransmitter receptor activity / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / regulation of vasoconstriction / Adenylate cyclase inhibitory pathway / behavioral fear response / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / adenylate cyclase-activating adrenergic receptor signaling pathway / regulation of mitotic spindle organization / cellular response to forskolin / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Regulation of insulin secretion / G protein-coupled receptor binding / electron transport chain / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / response to peptide hormone / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / GDP binding / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / cell cortex / midbody / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / chemical synaptic transmission / cell population proliferation / Ras protein signal transduction / Extra-nuclear estrogen signaling / periplasmic space / electron transfer activity / iron ion binding / cell cycle / G protein-coupled receptor signaling pathway / cell division / lysosomal membrane / GTPase activity / centrosome / synapse / dendrite / heme binding / positive regulation of cell population proliferation / protein-containing complex binding Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / Mus musculus (house mouse) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.0 Å | |||||||||
Authors | Chen Z / Xu P / Huang S / Xu HE / Wang S | |||||||||
Funding support | China, 1 items
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Citation | Journal: Cell / Year: 2024 Title: Flexible scaffold-based cheminformatics approach for polypharmacological drug design. Authors: Zhangcheng Chen / Jing Yu / Huan Wang / Peiyu Xu / Luyu Fan / Fengxiu Sun / Sijie Huang / Pei Zhang / He Huang / Shuo Gu / Bowen Zhang / Yue Zhou / Xiaobo Wan / Gang Pei / H Eric Xu / ...Authors: Zhangcheng Chen / Jing Yu / Huan Wang / Peiyu Xu / Luyu Fan / Fengxiu Sun / Sijie Huang / Pei Zhang / He Huang / Shuo Gu / Bowen Zhang / Yue Zhou / Xiaobo Wan / Gang Pei / H Eric Xu / Jianjun Cheng / Sheng Wang / Abstract: Effective treatments for complex central nervous system (CNS) disorders require drugs with polypharmacology and multifunctionality, yet designing such drugs remains a challenge. Here, we present a ...Effective treatments for complex central nervous system (CNS) disorders require drugs with polypharmacology and multifunctionality, yet designing such drugs remains a challenge. Here, we present a flexible scaffold-based cheminformatics approach (FSCA) for the rational design of polypharmacological drugs. FSCA involves fitting a flexible scaffold to different receptors using different binding poses, as exemplified by IHCH-7179, which adopted a "bending-down" binding pose at 5-HTR to act as an antagonist and a "stretching-up" binding pose at 5-HTR to function as an agonist. IHCH-7179 demonstrated promising results in alleviating cognitive deficits and psychoactive symptoms in mice by blocking 5-HTR for psychoactive symptoms and activating 5-HTR to alleviate cognitive deficits. By analyzing aminergic receptor structures, we identified two featured motifs, the "agonist filter" and "conformation shaper," which determine ligand binding pose and predict activity at aminergic receptors. With these motifs, FSCA can be applied to the design of polypharmacological ligands at other receptors. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_36634.map.gz | 96.2 MB | EMDB map data format | |
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Header (meta data) | emd-36634-v30.xml emd-36634.xml | 20.8 KB 20.8 KB | Display Display | EMDB header |
Images | emd_36634.png | 67.9 KB | ||
Filedesc metadata | emd-36634.cif.gz | 6.8 KB | ||
Others | emd_36634_half_map_1.map.gz emd_36634_half_map_2.map.gz | 80.9 MB 80.9 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-36634 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-36634 | HTTPS FTP |
-Validation report
Summary document | emd_36634_validation.pdf.gz | 977.7 KB | Display | EMDB validaton report |
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Full document | emd_36634_full_validation.pdf.gz | 977.3 KB | Display | |
Data in XML | emd_36634_validation.xml.gz | 13.1 KB | Display | |
Data in CIF | emd_36634_validation.cif.gz | 15.3 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-36634 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-36634 | HTTPS FTP |
-Related structure data
Related structure data | 8jt6MC 8jt8C 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_36634.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 0.84 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #1
File | emd_36634_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_36634_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
+Entire : 5-HT1A-Gi in complex with compound (R)-IHCH-7179
+Supramolecule #1: 5-HT1A-Gi in complex with compound (R)-IHCH-7179
+Macromolecule #1: Guanine nucleotide-binding protein G(i) subunit alpha-1
+Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+Macromolecule #3: ScFv16
+Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+Macromolecule #5: Soluble cytochrome b562,5-hydroxytryptamine receptor 1A
+Macromolecule #6: CHOLESTEROL
+Macromolecule #7: PALMITIC ACID
+Macromolecule #8: [(2R)-1-[oxidanyl-[(2R,3R,5S,6R)-2,3,5,6-tetrakis(oxidanyl)-4-pho...
+Macromolecule #9: 1-(4-fluorophenyl)-4-[(7R)-2,5,11-triazatetracyclo[7.6.1.0^2,7.0^...
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE-PROPANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 70.0 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: 2.2 µm / Nominal defocus min: 1.2 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: EMDB MAP EMDB ID: |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 175082 |
Initial angle assignment | Type: RANDOM ASSIGNMENT |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |