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Yorodumi- EMDB-26598: CryoEM structure of Go-coupled 5-HT5AR in complex with Lisuride -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-26598 | |||||||||
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Title | CryoEM structure of Go-coupled 5-HT5AR in complex with Lisuride | |||||||||
Map data | primary map | |||||||||
Sample |
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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 / Olfactory Signaling Pathway / Activation of the phototransduction cascade ...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 / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / 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 / 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 / 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 / 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 / response to estradiol / retina development in camera-type eye / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / chemical synaptic transmission / perikaryon / Extra-nuclear estrogen signaling / cell population proliferation / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / dendrite / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytoplasm / cytosol Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / Mus musculus (house mouse) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.79 Å | |||||||||
Authors | Zhang S / Fay JF / Roth BL | |||||||||
Funding support | United States, 2 items
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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
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_26598.map.gz | 54.5 MB | EMDB map data format | |
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Header (meta data) | emd-26598-v30.xml emd-26598.xml | 21.3 KB 21.3 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_26598_fsc.xml | 13.9 KB | Display | FSC data file |
Images | emd_26598.png | 67.2 KB | ||
Masks | emd_26598_msk_1.map | 64 MB | Mask map | |
Others | emd_26598_half_map_1.map.gz emd_26598_half_map_2.map.gz | 59.4 MB 59.4 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-26598 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-26598 | HTTPS FTP |
-Validation report
Summary document | emd_26598_validation.pdf.gz | 706.4 KB | Display | EMDB validaton report |
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Full document | emd_26598_full_validation.pdf.gz | 706 KB | Display | |
Data in XML | emd_26598_validation.xml.gz | 18.3 KB | Display | |
Data in CIF | emd_26598_validation.cif.gz | 24.3 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-26598 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-26598 | HTTPS FTP |
-Related structure data
Related structure data | 7um6MC 7um4C 7um5C 7um7C 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 |
EM raw data | EMPIAR-11036 (Title: CryoEM structure of Go-coupled 5-HT5AR in complex with Lisuride Data size: 406.8 Data #1: Aligned multi-frame micrographs [micrographs - single frame]) |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_26598.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Annotation | primary map | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.91 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
File | emd_26598_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: half map A
File | emd_26598_half_map_1.map | ||||||||||||
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Annotation | half map A | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: half map B
File | emd_26598_half_map_2.map | ||||||||||||
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Annotation | half map B | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Go-coupled 5-HT5AR complex
Entire | Name: Go-coupled 5-HT5AR complex |
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Components |
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-Supramolecule #1: Go-coupled 5-HT5AR complex
Supramolecule | Name: Go-coupled 5-HT5AR complex / type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#5 |
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-Supramolecule #2: 5-hydroxytryptamine receptor 5A, miniGo protein, Guanine nucleoti...
Supramolecule | Name: 5-hydroxytryptamine receptor 5A, miniGo protein, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 type: complex / Chimera: Yes / ID: 2 / Parent: 1 / Macromolecule list: #1-#4 |
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Source (natural) | Organism: Homo sapiens (human) |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
-Supramolecule #3: Single-chain variable fragment scFv16
Supramolecule | Name: Single-chain variable fragment scFv16 / type: complex / Chimera: Yes / ID: 3 / Parent: 1 / Macromolecule list: #5 |
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Source (natural) | Organism: Mus musculus (house mouse) |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
-Macromolecule #1: 5-hydroxytryptamine receptor 5A
Macromolecule | Name: 5-hydroxytryptamine receptor 5A / 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: 36.884168 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: SSPLLSVFGV LILTLLGFLV AATFAWNLLV LATILRVRTF HRVPHNLVAS MAVSDVLVAA LVMPLSLVHE LSGRRWQLGR RLCQLWIAC DVLCCTASIW NVTAIALDRY WSITRPMEYT LRTRKCVSNV MIALTWALSA VISLAPLLFG WGETYSEGSE E CQVSREPS ...String: SSPLLSVFGV LILTLLGFLV AATFAWNLLV LATILRVRTF HRVPHNLVAS MAVSDVLVAA LVMPLSLVHE LSGRRWQLGR RLCQLWIAC DVLCCTASIW NVTAIALDRY WSITRPMEYT LRTRKCVSNV MIALTWALSA VISLAPLLFG WGETYSEGSE E CQVSREPS YAVFSTVGAF YLPLCVVLFV YWKIYKAAKF RVGSRKTNSV SPISEAVEVK DSAKQPQMVF TVRHATVTFQ PE GDTWREQ KEQRAALMVG ILIGVFVLCW IPFFLTELIS PLCSCDIPAI WKSIFLWLGY SNSFFNPLIY TAFNKNYNSA FKN FFSRQH |
-Macromolecule #2: miniGo protein
Macromolecule | Name: miniGo protein / 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: 25.159777 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: TLSAEDKAAV ERSKMIEKNL KEDGISAAKD VKLLLLGADN SGKSTIVKQM KIIHGGSGGS GGTTGIVETH FTFKNLHFRL FDVGGQRSE RKKWIHCFED VTAIIFCVDL SDYNRMHESL MLFDSICNNK FFIDTSIILF LNKKDLFGEK IKKSPLTICF P EYTGPNTY ...String: TLSAEDKAAV ERSKMIEKNL KEDGISAAKD VKLLLLGADN SGKSTIVKQM KIIHGGSGGS GGTTGIVETH FTFKNLHFRL FDVGGQRSE RKKWIHCFED VTAIIFCVDL SDYNRMHESL MLFDSICNNK FFIDTSIILF LNKKDLFGEK IKKSPLTICF P EYTGPNTY EDAAAYIQAQ FESKNRSPNK EIYCHMTCAT DTNNAQVIFD AVTDIIIANN LRGCGLY |
-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: 37.285734 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: SELDQLRQEA EQLKNQIRDA RKACADATLS QITNNIDPVG RIQMRTRRTL RGHLAKIYAM HWGTDSRLLV SASQDGKLII WDSYTTNKV HAIPLRSSWV MTCAYAPSGN YVACGGLDNI CSIYNLKTRE GNVRVSRELA GHTGYLSCCR FLDDNQIVTS S GDTTCALW ...String: SELDQLRQEA EQLKNQIRDA RKACADATLS QITNNIDPVG RIQMRTRRTL RGHLAKIYAM HWGTDSRLLV SASQDGKLII WDSYTTNKV HAIPLRSSWV MTCAYAPSGN YVACGGLDNI CSIYNLKTRE GNVRVSRELA GHTGYLSCCR FLDDNQIVTS S GDTTCALW DIETGQQTTT FTGHTGDVMS LSLAPDTRLF VSGACDASAK LWDVREGMCR QTFTGHESDI NAICFFPNGN AF ATGSDDA TCRLFDLRAD QELMTYSHDN IICGITSVSF SKSGRLLLAG YDDFNCNVWD ALKADRAGVL AGHDNRVSCL GVT DDGMAV ATGSWDSFLK IWN |
-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-chain variable fragment scFv16
Macromolecule | Name: Single-chain variable fragment scFv16 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Mus musculus (house mouse) |
Molecular weight | Theoretical: 26.679721 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 KAAA |
-Macromolecule #6: N,N-diethyl-N'-[(8alpha)-6-methyl-9,10-didehydroergolin-8-yl]urea
Macromolecule | Name: N,N-diethyl-N'-[(8alpha)-6-methyl-9,10-didehydroergolin-8-yl]urea type: ligand / ID: 6 / Number of copies: 1 / Formula: H8G |
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Molecular weight | Theoretical: 338.447 Da |
Chemical component information | ChemComp-H8G: |
-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 TECNAI 10 |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 43.8 e/Å2 |
Electron beam | Acceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.211 µm / Nominal defocus min: 0.14300000000000002 µm |