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Yorodumi- EMDB-35657: Cryo-EM structure of Carboprost-bound prostaglandin-F2-alpha rece... -
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-Basic information
Entry | Database: EMDB / ID: EMD-35657 | |||||||||
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Title | Cryo-EM structure of Carboprost-bound prostaglandin-F2-alpha receptor-miniGq-Nb35 complex | |||||||||
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Keywords | GPCR / Complex / Prostaglandin receptor / Agonist / MEMBRANE PROTEIN | |||||||||
Function / homology | Function and homology information prostaglandin F receptor activity / parturition / Prostanoid ligand receptors / cellular response to prostaglandin D stimulus / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors ...prostaglandin F receptor activity / parturition / Prostanoid ligand receptors / cellular response to prostaglandin D stimulus / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Glucagon signaling in metabolic regulation / 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 / G beta:gamma signalling through CDC42 / Vasopressin regulates renal water homeostasis via Aquaporins / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / G alpha (z) signalling events / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / GPER1 signaling / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / response to estradiol / GTPase binding / retina development in camera-type eye / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / response to lipopolysaccharide / cell population proliferation / Extra-nuclear estrogen signaling / inflammatory response / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / positive regulation of cell population proliferation / protein-containing complex binding / positive regulation of gene expression / negative regulation of apoptotic process / signal transduction / extracellular exosome / extracellular region / membrane / plasma membrane / cytosol / cytoplasm Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / Vicugna pacos (alpaca) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.7 Å | |||||||||
Authors | Lv X / Gao K / Nie J / Zhang X / Zhang S / Ren Y / Li Q / Huang J / Liu L / Sun X ...Lv X / Gao K / Nie J / Zhang X / Zhang S / Ren Y / Li Q / Huang J / Liu L / Sun X / Zhang W / Liu X | |||||||||
Funding support | China, 1 items
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Citation | Journal: Nat Commun / Year: 2023 Title: Structures of human prostaglandin F receptor reveal the mechanism of ligand and G protein selectivity. Authors: Xiuqing Lv / Kaixuan Gao / Jia Nie / Xin Zhang / Shuhao Zhang / Yinhang Ren / Xiaoou Sun / Qi Li / Jingrui Huang / Lijuan Liu / Xiaowen Zhang / Weishe Zhang / Xiangyu Liu / Abstract: Prostaglandins and their receptors regulate various physiological processes. Carboprost, an analog of prostaglandin F and an agonist for the prostaglandin F2-alpha receptor (FP receptor), is ...Prostaglandins and their receptors regulate various physiological processes. Carboprost, an analog of prostaglandin F and an agonist for the prostaglandin F2-alpha receptor (FP receptor), is clinically used to treat postpartum hemorrhage (PPH). However, off-target activation of closely related receptors such as the prostaglandin E receptor subtype EP3 (EP3 receptor) by carboprost results in side effects and limits the clinical application. Meanwhile, the FP receptor selective agonist latanoprost is not suitable to treat PPH due to its poor solubility and fast clearance. Here, we present two cryo-EM structures of the FP receptor bound to carboprost and latanoprost-FA (the free acid form of latanoprost) at 2.7 Å and 3.2 Å resolution, respectively. The structures reveal the molecular mechanism of FP receptor selectivity for both endogenous prostaglandins and clinical drugs, as well as the molecular mechanism of G protein coupling preference by the prostaglandin receptors. The structural information may guide the development of better prostaglandin drugs. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_35657.map.gz | 59.6 MB | EMDB map data format | |
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Header (meta data) | emd-35657-v30.xml emd-35657.xml | 19.7 KB 19.7 KB | Display Display | EMDB header |
Images | emd_35657.png | 46.8 KB | ||
Masks | emd_35657_msk_1.map | 64 MB | Mask map | |
Filedesc metadata | emd-35657.cif.gz | 6.7 KB | ||
Others | emd_35657_half_map_1.map.gz emd_35657_half_map_2.map.gz | 59.4 MB 59.4 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-35657 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-35657 | HTTPS FTP |
-Validation report
Summary document | emd_35657_validation.pdf.gz | 783.2 KB | Display | EMDB validaton report |
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Full document | emd_35657_full_validation.pdf.gz | 782.7 KB | Display | |
Data in XML | emd_35657_validation.xml.gz | 12.3 KB | Display | |
Data in CIF | emd_35657_validation.cif.gz | 14.5 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-35657 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-35657 | HTTPS FTP |
-Related structure data
Related structure data | 8iq4MC 8iq6C 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_35657.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.0979 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
File | emd_35657_msk_1.map | ||||||||||||
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Density Histograms |
-Half map: #1
File | emd_35657_half_map_1.map | ||||||||||||
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Density Histograms |
-Half map: #2
File | emd_35657_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Cryo-EM structure of Carboprost-bound prostaglandin-F2-alpha rece...
Entire | Name: Cryo-EM structure of Carboprost-bound prostaglandin-F2-alpha receptor-miniGq-Nb35 complex |
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Components |
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-Supramolecule #1: Cryo-EM structure of Carboprost-bound prostaglandin-F2-alpha rece...
Supramolecule | Name: Cryo-EM structure of Carboprost-bound prostaglandin-F2-alpha receptor-miniGq-Nb35 complex type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Prostaglandin F2-alpha receptor
Macromolecule | Name: Prostaglandin F2-alpha receptor / 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: 42.909363 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: DYKDDDDAMS MNNSKQLVSP AAALLSNTTC QTENRLSVFF SVIFMTVGIL SNSLAIAILM KAYQRFRQKS KASFLLLASG LVITDFFGH LINGAIAVFV YASDKEWIRF DQSNVLCSIF GICMVFSGLC PLLLGSVMAI ERCIGVTKPI FHSTKITSKH V KMMLSGVC ...String: DYKDDDDAMS MNNSKQLVSP AAALLSNTTC QTENRLSVFF SVIFMTVGIL SNSLAIAILM KAYQRFRQKS KASFLLLASG LVITDFFGH LINGAIAVFV YASDKEWIRF DQSNVLCSIF GICMVFSGLC PLLLGSVMAI ERCIGVTKPI FHSTKITSKH V KMMLSGVC LFAVFIALLP ILGHRDYKIQ ASRTWCFYNT EDIKDWEDRF YLLLFSFLGL LALGVSLLCN AITGITLLRV KF KSQQHRQ GRSHHLEMVI QLLAIMCVSC ICWSPFLVTM ANIGINGNHS LETCETTLFA LRMATWNQIL DPWVYILLRK AVL KNLYKL ASQCCGVHVI SLHIWELSSI KNSLKVAAIS ESPVAEKSAS THHHHHHGGS GGLEVLFQ UniProtKB: Prostaglandin F2-alpha receptor |
-Macromolecule #2: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Macromolecule | Name: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short 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: 28.168926 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: GPTLSAEDKA AVERSKMIEK QLQKDKQVYR ATHRLLLLGA DNSGKSTIVK QMRILHGGSG GSGGTSGIFE TKFQVDKVNF HMFDVGGQR DERRKWIQCF NDVTAIIFVV DSSDYNRLQE ALNDFKSIWN NRWLRTISVI LFLNKQDLLA EKVLAGKSKI E DYFPEFAR ...String: GPTLSAEDKA AVERSKMIEK QLQKDKQVYR ATHRLLLLGA DNSGKSTIVK QMRILHGGSG GSGGTSGIFE TKFQVDKVNF HMFDVGGQR DERRKWIQCF NDVTAIIFVV DSSDYNRLQE ALNDFKSIWN NRWLRTISVI LFLNKQDLLA EKVLAGKSKI E DYFPEFAR YTTPEDATPE PGEDPRVTRA KYFIRDEFLR ISTASGDGRH YCYPHFTCAV DTENARRIFN DCKDIILQMN LR EYNLV UniProtKB: UNIPROTKB: P63092, UNIPROTKB: P63092 |
-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: Trichoplusia ni (cabbage looper) |
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 UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-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: Trichoplusia ni (cabbage looper) |
Sequence | String: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-Macromolecule #5: Nanobody 35
Macromolecule | Name: Nanobody 35 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Vicugna pacos (alpaca) |
Molecular weight | Theoretical: 14.686328 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: QVQLQESGGG LVQPGGSLRL SCAASGFTFS NYKMNWVRQA PGKGLEWVSD ISQSGASISY TGSVKGRFTI SRDNAKNTLY LQMNSLKPE DTAVYYCARC PAPFTPFCFD VTSTTYAYRG QGTQVTVSSH HHHHH |
-Macromolecule #6: Z-7-[(1R,2R,3R,5S)-2-[(E,3S)-3-methyl-3-oxidanyl-oct-1-enyl]-3,5-...
Macromolecule | Name: Z-7-[(1R,2R,3R,5S)-2-[(E,3S)-3-methyl-3-oxidanyl-oct-1-enyl]-3,5-bis(oxidanyl)cyclopentyl]hept-5-enoic acid type: ligand / ID: 6 / Number of copies: 1 / Formula: 87Q |
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Molecular weight | Theoretical: 368.508 Da |
Chemical component information | ChemComp-87Q: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.45 |
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Grid | Material: GOLD |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k 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: 1.8 µm / Nominal defocus min: 1.1 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: NONE |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 327293 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |