+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-38095 | |||||||||
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Title | MRE-269 bound Prostacyclin Receptor G protein complex | |||||||||
Map data | ||||||||||
Sample |
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Keywords | Agonist / Complex / lipid receptor / SIGNALING PROTEIN | |||||||||
Function / homology | Function and homology information prostacyclin receptor activity / Prostanoid ligand receptors / negative regulation of platelet-derived growth factor receptor signaling pathway / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / G-protein beta/gamma-subunit complex binding / guanyl-nucleotide exchange factor activity / adenylate cyclase-activating G protein-coupled receptor signaling pathway / negative regulation of smooth muscle cell proliferation / Olfactory Signaling Pathway / Activation of the phototransduction cascade ...prostacyclin receptor activity / Prostanoid ligand receptors / negative regulation of platelet-derived growth factor receptor signaling pathway / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / G-protein beta/gamma-subunit complex binding / guanyl-nucleotide exchange factor activity / adenylate cyclase-activating G protein-coupled receptor signaling pathway / negative regulation of smooth muscle cell proliferation / 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) / cell-cell signaling / 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 / GTP binding / protein-containing complex binding / signal transduction / extracellular exosome / membrane / metal ion binding / plasma membrane / cytosol / cytoplasm Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.41 Å | |||||||||
Authors | Wang JJ / Jin S / Zhang H / Xu Y / Hu W / Jiang Y / Chen C / Wang DW / Xu HE / Wu C | |||||||||
Funding support | China, 1 items
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Citation | Journal: Sci Adv / Year: 2024 Title: Molecular recognition and activation of the prostacyclin receptor by anti-pulmonary arterial hypertension drugs. Authors: James Jiqi Wang / Sanshan Jin / Heng Zhang / Youwei Xu / Wen Hu / Yi Jiang / Chen Chen / Dao Wen Wang / H Eric Xu / Canrong Wu / Abstract: The prostacyclin (PGI) receptor (IP) is a G-coupled receptor associated with blood pressure regulation, allergy, and inflammatory response. It is a main therapeutic target for pulmonary arterial ...The prostacyclin (PGI) receptor (IP) is a G-coupled receptor associated with blood pressure regulation, allergy, and inflammatory response. It is a main therapeutic target for pulmonary arterial hypertension (PAH) and several other diseases. Here we report cryo-electron microscopy (cryo-EM) structures of the human IP-G complex bound with two anti-PAH drugs, treprostinil and MRE-269 (active form of selexipag), at global resolutions of 2.56 and 2.41 angstrom, respectively. These structures revealed distinct features governing IP ligand binding, receptor activation, and G protein coupling. Moreover, comparison of the activated IP structures uncovered the mechanism and key residues that determine the superior selectivity of MRE-269 over treprostinil. Combined with molecular docking and functional studies, our structures provide insight into agonist selectivity, ligand recognition, receptor activation, and G protein coupling. Our results provide a structural template for further improving IP-targeting drugs to reduce off-target activation of prostanoid receptors and adverse effects. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_38095.map.gz | 115.9 MB | EMDB map data format | |
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Header (meta data) | emd-38095-v30.xml emd-38095.xml | 21.3 KB 21.3 KB | Display Display | EMDB header |
Images | emd_38095.png | 51.3 KB | ||
Filedesc metadata | emd-38095.cif.gz | 6.5 KB | ||
Others | emd_38095_additional_1.map.gz emd_38095_half_map_1.map.gz emd_38095_half_map_2.map.gz | 117.8 MB 115.9 MB 115.9 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-38095 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-38095 | HTTPS FTP |
-Validation report
Summary document | emd_38095_validation.pdf.gz | 1.5 MB | Display | EMDB validaton report |
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Full document | emd_38095_full_validation.pdf.gz | 1.5 MB | Display | |
Data in XML | emd_38095_validation.xml.gz | 13.7 KB | Display | |
Data in CIF | emd_38095_validation.cif.gz | 16.2 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-38095 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-38095 | HTTPS FTP |
-Related structure data
Related structure data | 8x79MC 8x7aC 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_38095.map.gz / Format: CCP4 / Size: 125 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: 0.73 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Additional map: #1
File | emd_38095_additional_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_38095_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_38095_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : IP-Gs complex
Entire | Name: IP-Gs complex |
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Components |
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-Supramolecule #1: IP-Gs complex
Supramolecule | Name: IP-Gs complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #5, #1-#4 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Guanine nucleotide-binding protein G(s) subunit alpha isoforms sh...
Macromolecule | Name: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short,GNAS complex locus,GNAS complex locus 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: 29.068906 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MNSKTEDQRN EEKAQREANK KIEKQLQKDK QVYRATHRLL LLGADNSGKS TIVKQMRILH GGSGGSGGTS GIFETKFQVD KVNFHMFDV GAQRDERRKW IQCFNDVTAI IFVVDSSDYN RLQEALNLFK SIWNNRWLRT ISVILFLNKQ DLLAEKVLAG K SKIEDYFP ...String: MNSKTEDQRN EEKAQREANK KIEKQLQKDK QVYRATHRLL LLGADNSGKS TIVKQMRILH GGSGGSGGTS GIFETKFQVD KVNFHMFDV GAQRDERRKW IQCFNDVTAI IFVVDSSDYN RLQEALNLFK SIWNNRWLRT ISVILFLNKQ DLLAEKVLAG K SKIEDYFP EFARYTTPED ATPEPGEDPR VTRAKYFIRD EFLRISTASG DGRHYCYPHF TCSVDTENAR RIFNDCRDII QR MHLRQYE LL UniProtKB: Guanine nucleotide-binding protein G(s) subunit alpha |
-Macromolecule #2: 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: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 38.613176 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: HHHHHHGSLL QSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKL IIWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC R FLDDNQIV ...String: HHHHHHGSLL QSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKL IIWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC R FLDDNQIV TSSGDTTCAL WDIETGQQTT TFTGHTGDVM SLSLAPDTRL FVSGACDASA KLWDVREGMC RQTFTGHESD IN AICFFPN GNAFATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAG HDNRVS CLGVTDDGMA VATGSWDSFL KIWN UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-Macromolecule #3: 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: 3 / 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 UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-Macromolecule #4: Nanobody35
Macromolecule | Name: Nanobody35 / 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: 14.71432 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: QVQLQESGGG LVQPGGSLRL SCAASGFTFS NYKMNWVRQA PGKGLEWVSD ISQSGASISY TGSVKGRFTI SRDNAKNTLY LQMNSLKPE DTAVYYCARC PAPFTRDCFD VTSTTYAYRG QGTQVTVSSH HHHHH |
-Macromolecule #5: Prostacyclin receptor
Macromolecule | Name: Prostacyclin receptor / 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: 40.989914 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MADSCRNLTY VRGSVGPATS TLMFVAGVVG NGLALGILSA RRPARPSAFA VLVTGLAATD LLGTSFLSPA VFVAYARNSS LLGLARGGP ALCDAFAFAM TFFGLASMLI LFAMAVERCL ALSHPYLYAQ LDGPRCARLA LPAIYAFCVL FCALPLLGLG Q HQQYCPGS ...String: MADSCRNLTY VRGSVGPATS TLMFVAGVVG NGLALGILSA RRPARPSAFA VLVTGLAATD LLGTSFLSPA VFVAYARNSS LLGLARGGP ALCDAFAFAM TFFGLASMLI LFAMAVERCL ALSHPYLYAQ LDGPRCARLA LPAIYAFCVL FCALPLLGLG Q HQQYCPGS WCFLRMRWAQ PGGAAFSLAY AGLVALLVAA IFLCNGSVTL SLCRMYRQQK RHQGSLGPRP RTGEDEVDHL IL LALMTVV MAVCSLPLTI RCFTQAVAPD SSSEMGDLLA FRFYAFNPIL DPWVFILFRK AVFQRLKLWV CCLCLGPAHG DSQ TPLSQL ASGRRDPRAP SAPVGKEGSC VPLSAWGEGQ VEPLPPTQQS SGSAVGTSSK AEASVACSLC UniProtKB: Prostacyclin receptor |
-Macromolecule #6: 2-[4-[(5,6-diphenylpyrazin-2-yl)-propan-2-yl-amino]butoxy]ethanoi...
Macromolecule | Name: 2-[4-[(5,6-diphenylpyrazin-2-yl)-propan-2-yl-amino]butoxy]ethanoic acid type: ligand / ID: 6 / Number of copies: 1 / Formula: Y9Q |
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Molecular weight | Theoretical: 419.516 Da |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 5.0 µm / Nominal defocus min: 1.2 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: PDB ENTRY PDB model - PDB ID: |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.41 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 206075 |
Initial angle assignment | Type: ANGULAR RECONSTITUTION |
Final angle assignment | Type: ANGULAR RECONSTITUTION |
-Atomic model buiding 1
Refinement | Protocol: OTHER |
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Output model | PDB-8x79: |