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Yorodumi- EMDB-21669: HTR2A bound to 25-CN-NBOH in complex with a mini-Galpha-q protein... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-21669 | |||||||||
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Title | HTR2A bound to 25-CN-NBOH in complex with a mini-Galpha-q protein, beta/gamma subunits and an active-state stabilizing single-chain variable fragment (scFv16) obtained by cryo-electron microscopy (cryoEM) | |||||||||
Map data | HTR2A bound to 25-CN-NBOH in complex with a mini-G%u237Aq protein, %u03B2/%uD835%uDEFE subunits and an active-state stabilizing single-chain variable fragment (scFv16) obtained by cryo-electron microscopy (cryoEM) | |||||||||
Sample |
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Function / homology | Function and homology information positive regulation of heat generation / protein localization to cytoskeleton / 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding / Gq/11-coupled serotonin receptor activity / phospholipase C-activating serotonin receptor signaling pathway / positive regulation of phosphatidylinositol biosynthetic process / G protein-coupled serotonin receptor signaling pathway / G protein-coupled serotonin receptor complex / neurofilament / positive regulation of cytokine production involved in immune response ...positive regulation of heat generation / protein localization to cytoskeleton / 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding / Gq/11-coupled serotonin receptor activity / phospholipase C-activating serotonin receptor signaling pathway / positive regulation of phosphatidylinositol biosynthetic process / G protein-coupled serotonin receptor signaling pathway / G protein-coupled serotonin receptor complex / neurofilament / positive regulation of cytokine production involved in immune response / artery smooth muscle contraction / Serotonin receptors / cell body fiber / serotonin receptor signaling pathway / sensitization / urinary bladder smooth muscle contraction / protein tyrosine kinase activator activity / serotonin binding / negative regulation of synaptic transmission, glutamatergic / G protein-coupled serotonin receptor activity / positive regulation of platelet aggregation / : / neurotransmitter receptor activity / temperature homeostasis / positive regulation of DNA biosynthetic process / positive regulation of fat cell differentiation / regulation of dopamine secretion / positive regulation of execution phase of apoptosis / negative regulation of potassium ion transport / detection of temperature stimulus involved in sensory perception of pain / behavioral response to cocaine / positive regulation of vasoconstriction / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / detection of mechanical stimulus involved in sensory perception of pain / release of sequestered calcium ion into cytosol / presynaptic modulation of chemical synaptic transmission / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of glycolytic process / dendritic shaft / caveola / glycolytic process / electron transport chain / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / 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 / memory / 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 / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / intracellular calcium ion homeostasis / G alpha (z) signalling events / positive regulation of inflammatory response / 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 / positive regulation of peptidyl-tyrosine phosphorylation / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / positive regulation of neuron apoptotic process / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / virus receptor activity / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway / presynaptic membrane / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / G alpha (i) signalling events / fibroblast proliferation / cytoplasmic vesicle / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / chemical synaptic transmission / postsynaptic membrane Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.36 Å | |||||||||
Authors | Skiniotis G / Roth B / Kim K / Panova O | |||||||||
Funding support | United States, 2 items
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Citation | Journal: Cell / Year: 2020 Title: Structure of a Hallucinogen-Activated Gq-Coupled 5-HT Serotonin Receptor. Authors: Kuglae Kim / Tao Che / Ouliana Panova / Jeffrey F DiBerto / Jiankun Lyu / Brian E Krumm / Daniel Wacker / Michael J Robertson / Alpay B Seven / David E Nichols / Brian K Shoichet / Georgios ...Authors: Kuglae Kim / Tao Che / Ouliana Panova / Jeffrey F DiBerto / Jiankun Lyu / Brian E Krumm / Daniel Wacker / Michael J Robertson / Alpay B Seven / David E Nichols / Brian K Shoichet / Georgios Skiniotis / Bryan L Roth / Abstract: Hallucinogens like lysergic acid diethylamide (LSD), psilocybin, and substituted N-benzyl phenylalkylamines are widely used recreationally with psilocybin being considered as a therapeutic for many ...Hallucinogens like lysergic acid diethylamide (LSD), psilocybin, and substituted N-benzyl phenylalkylamines are widely used recreationally with psilocybin being considered as a therapeutic for many neuropsychiatric disorders including depression, anxiety, and substance abuse. How psychedelics mediate their actions-both therapeutic and hallucinogenic-are not understood, although activation of the 5-HT serotonin receptor (HTR2A) is key. To gain molecular insights into psychedelic actions, we determined the active-state structure of HTR2A bound to 25-CN-NBOH-a prototypical hallucinogen-in complex with an engineered Gαq heterotrimer by cryoelectron microscopy (cryo-EM). We also obtained the X-ray crystal structures of HTR2A complexed with the arrestin-biased ligand LSD or the inverse agonist methiothepin. Comparisons of these structures reveal determinants responsible for HTR2A-Gαq protein interactions as well as the conformational rearrangements involved in active-state transitions. Given the potential therapeutic actions of hallucinogens, these findings could accelerate the discovery of more selective drugs for the treatment of a variety of neuropsychiatric disorders. | |||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_21669.map.gz | 3.4 MB | EMDB map data format | |
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Header (meta data) | emd-21669-v30.xml emd-21669.xml | 19.6 KB 19.6 KB | Display Display | EMDB header |
Images | emd_21669.png | 44.8 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-21669 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-21669 | HTTPS FTP |
-Validation report
Summary document | emd_21669_validation.pdf.gz | 350.1 KB | Display | EMDB validaton report |
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Full document | emd_21669_full_validation.pdf.gz | 349.7 KB | Display | |
Data in XML | emd_21669_validation.xml.gz | 5.8 KB | Display | |
Data in CIF | emd_21669_validation.cif.gz | 6.5 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-21669 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-21669 | HTTPS FTP |
-Related structure data
Related structure data | 6whaMC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_21669.map.gz / Format: CCP4 / Size: 28.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | HTR2A bound to 25-CN-NBOH in complex with a mini-G%u237Aq protein, %u03B2/%uD835%uDEFE subunits and an active-state stabilizing single-chain variable fragment (scFv16) obtained by cryo-electron microscopy (cryoEM) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.8521 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Sample components
-Entire : HTR2A bound to 25-CN-NBOH in complex with a mini-Galpha-q protein...
Entire | Name: HTR2A bound to 25-CN-NBOH in complex with a mini-Galpha-q protein, beta/gamma subunits and an active-state stabilizing single-chain variable fragment (scFv16) obtained by cryo-electron microscopy (cryoEM) |
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Components |
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-Supramolecule #1: HTR2A bound to 25-CN-NBOH in complex with a mini-Galpha-q protein...
Supramolecule | Name: HTR2A bound to 25-CN-NBOH in complex with a mini-Galpha-q protein, beta/gamma subunits and an active-state stabilizing single-chain variable fragment (scFv16) obtained by cryo-electron microscopy (cryoEM) type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5 |
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Source (natural) | Organism: Homo sapiens (human) |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
-Macromolecule #1: Soluble cytochrome b562,5-hydroxytryptamine receptor 2A chimera
Macromolecule | Name: Soluble cytochrome b562,5-hydroxytryptamine receptor 2A chimera type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 56.167309 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MKTIIALSYI FCLVFADYKD DDDAKLQTMH HHHHHHHHHE NLYFQGGTTM ADLEDNWETL NDNLKVIEKA DNAAQVKDAL TKMRAAALD AQKATPPKLE DKSPDSPEMK DFRHGFDILV GQIDDALKLA NEGKVKEAQA AAEQLKTTRN AYIQKYLGSL S LLHLQEKN ...String: MKTIIALSYI FCLVFADYKD DDDAKLQTMH HHHHHHHHHE NLYFQGGTTM ADLEDNWETL NDNLKVIEKA DNAAQVKDAL TKMRAAALD AQKATPPKLE DKSPDSPEMK DFRHGFDILV GQIDDALKLA NEGKVKEAQA AAEQLKTTRN AYIQKYLGSL S LLHLQEKN WSALLTAVVI ILTIAGNILV IMAVSLEKKL QNATNYFLMS LAIADMLLGF LVMPVSMLTI LYGYRWPLPS KL CAVWIYL DVLFSTASIM HLCAISLDRY VAIQNPIHHS RFNSRTKAFL KIIAVWTISV GISMPIPVFG LQDDSKVFKE GSC LLADDN FVLIGSFVSF FIPLTIMVIT YFLTIKSLQK EATLCVSDLG TRAKLASFSF LPQSSLSSEK LFQRSIHREP GSYT GRRTM QSISNEQKAC KVLGIVFFLF VVMWCPFFIT NIMAVICKES CNEDVIGALL NVFVWIGYLS SAVNPLVYTL FNKTY RSAF SRYIQCQYKE NKK |
-Macromolecule #2: G subunit q (Gi2-mini-Gq chimeric)
Macromolecule | Name: G subunit q (Gi2-mini-Gq chimeric) / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 28.084832 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MGSTVSAEDK AAAERSKMID KNLREDGEKA RRTLRLLLLG ADNSGKSTIV KQMRILHGGS GGSGGTSGIF ETKFQVDKVN FHMFDVGGQ RDERRKWIQC FNDVTAIIFV VDSSDYNRLQ EALNDFKSIW NNRWLRTISV ILFLNKQDLL AEKVLAGKSK I EDYFPEFA ...String: MGSTVSAEDK AAAERSKMID KNLREDGEKA RRTLRLLLLG ADNSGKSTIV KQMRILHGGS GGSGGTSGIF ETKFQVDKVN FHMFDVGGQ RDERRKWIQC FNDVTAIIFV VDSSDYNRLQ EALNDFKSIW NNRWLRTISV ILFLNKQDLL AEKVLAGKSK I EDYFPEFA RYTTPEDATP EPGEDPRVTR AKYFIRKEFV DISTASGDGR HICYPHFTCA VDTENARRIF NDCKDIILQM NL REYNLV |
-Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 39.418086 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MHHHHHHLEV LFQGPGSSGS ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLV SASQDGKLII WDSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG H TGYLSCCR ...String: MHHHHHHLEV LFQGPGSSGS ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLV SASQDGKLII WDSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG H TGYLSCCR FLDDNQIVTS SGDTTCALWD IETGQQTTTF TGHTGDVMSL SLAPDTRLFV SGACDASAKL WDVREGMCRQ TF TGHESDI NAICFFPNGN AFATGSDDAT CRLFDLRADQ ELMTYSHDNI ICGITSVSFS KSGRLLLAGY DDFNCNVWDA LKA DRAGVL AGHDNRVSCL GVTDDGMAVA TGSWDSFLKI WN |
-Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 7.861143 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L |
-Macromolecule #5: single Fab chain (svFv16)
Macromolecule | Name: single Fab chain (svFv16) / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 28.668922 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...String: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL KAAALEVLFQ GPHHHHHHHH |
-Macromolecule #6: 4-(2-{[(2-hydroxyphenyl)methyl]amino}ethyl)-2,5-dimethoxybenzonitrile
Macromolecule | Name: 4-(2-{[(2-hydroxyphenyl)methyl]amino}ethyl)-2,5-dimethoxybenzonitrile type: ligand / ID: 6 / Number of copies: 1 / Formula: U0G |
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Molecular weight | Theoretical: 312.363 Da |
Chemical component information | ChemComp-U0G: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 16.7 mg/mL | ||||||||||||||||||
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Buffer | pH: 7.5 Component:
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Grid | Model: Quantifoil R1.2/1.3 / Material: GOLD / Support film - Material: CARBON / Pretreatment - Type: GLOW DISCHARGE | ||||||||||||||||||
Vitrification | Cryogen name: ETHANE / Instrument: FEI VITROBOT MARK II |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 2368 / Average exposure time: 4.0 sec. / Average electron dose: 80.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | C2 aperture diameter: 70.0 µm / Calibrated defocus max: 2.5 µm / Calibrated defocus min: 1.0 µm / Calibrated magnification: 57050 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |