+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-39931 | |||||||||
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Title | Cryo-EM structure of the pasireotide-bound SSTR5-Gi complex | |||||||||
Map data | ||||||||||
Sample |
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Keywords | pasireotide / SSTR5 / Cryo-EM / MEMBRANE PROTEIN/IMMUNE SYSTEM / MEMBRANE PROTEIN-IMMUNE SYSTEM complex | |||||||||
Function / homology | Function and homology information somatostatin receptor activity / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Ca2+ pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding ...somatostatin receptor activity / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Ca2+ pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / neuropeptide binding / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G alpha (z) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Adrenaline,noradrenaline inhibits insulin secretion / beta2-adrenergic receptor activity / ADP signalling through P2Y purinoceptor 12 / positive regulation of mini excitatory postsynaptic potential / G alpha (q) signalling events / positive regulation of cAMP-dependent protein kinase activity / positive regulation of AMPA receptor activity / positive regulation of autophagosome maturation / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (i) signalling events / norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure / norepinephrine binding / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / heat generation / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / Adrenoceptors / ADP signalling through P2Y purinoceptor 12 / alkylglycerophosphoethanolamine phosphodiesterase activity / activation of transmembrane receptor protein tyrosine kinase activity / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / cellular response to glucocorticoid stimulus / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / negative regulation of smooth muscle contraction / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / positive regulation of lipophagy / G alpha (q) signalling events / photoreceptor outer segment membrane / negative regulation of multicellular organism growth / negative regulation of G protein-coupled receptor signaling pathway / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / spectrin binding / Vasopressin regulates renal water homeostasis via Aquaporins / response to psychosocial stress / endosome to lysosome transport / adrenergic receptor signaling pathway / diet induced thermogenesis / neuronal dense core vesicle / adenylate cyclase-activating adrenergic receptor signaling pathway / positive regulation of protein kinase A signaling / positive regulation of cytokinesis / regulation of insulin secretion / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / adenylate cyclase binding / neuropeptide signaling pathway / smooth muscle contraction / photoreceptor outer segment / potassium channel regulator activity / T cell migration / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / bone resorption / positive regulation of bone mineralization / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / brown fat cell differentiation / regulation of sodium ion transport / regulation of mitotic spindle organization / cardiac muscle cell apoptotic process / cellular response to forskolin / photoreceptor inner segment / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / response to cold / receptor-mediated endocytosis / G-protein beta/gamma-subunit complex binding / Peptide ligand-binding receptors / Regulation of insulin secretion / G protein-coupled receptor binding Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / Rattus norvegicus (Norway rat) / Bos taurus (cattle) / Oplophorus gracilirostris (crustacean) / synthetic construct (others) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.09 Å | |||||||||
Authors | Li YG / Meng XY / Yang XR / Ling SL / Shi P / Tian CL / Yang F | |||||||||
Funding support | 1 items
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Citation | Journal: Acta Pharmacol Sin / Year: 2024 Title: Structural insights into somatostatin receptor 5 bound with cyclic peptides. Authors: Ying-Ge Li / Xian-Yu Meng / Xiru Yang / Sheng-Long Ling / Pan Shi / Chang-Lin Tian / Fan Yang / Abstract: Somatostatin receptor 5 (SSTR5) is highly expressed in ACTH-secreting pituitary adenomas and is an important drug target for the treatment of Cushing's disease. Two cyclic SST analog peptides ...Somatostatin receptor 5 (SSTR5) is highly expressed in ACTH-secreting pituitary adenomas and is an important drug target for the treatment of Cushing's disease. Two cyclic SST analog peptides (pasireotide and octreotide) both can activate SSTR5 and SSTR2. Pasireotide is preferential binding to SSTR5 than octreotide, while octreotide is biased to SSTR2 than SSTR5. The lack of selectivity of both pasireotide and octreotide causes side effects, such as hyperglycemia, gastrointestinal disturbance, and abnormal glucose homeostasis. However, little is known about the binding and selectivity mechanisms of pasireotide and octreotide with SSTR5, limiting the development of subtype-selective SST analog drugs specifically targeting SSTR5. Here, we report two cryo-electron microscopy (cryo-EM) structures of SSTR5-Gi complexes activated by pasireotide and octreoitde at resolutions of 3.09 Å and 3.24 Å, respectively. In combination with structural analysis and functional experiments, our results reveal the molecular mechanisms of ligand recognition and receptor activation. We also demonstrate that pasireotide preferentially binds to SSTR5 through the interactions between Tyr(Bzl)/Trp of pasireotide and SSTR5. Moreover, we find that the Q, N, F and ECL2 of SSTR2 play a crucial role in octreotide biased binding of SSTR2. Our results will provide structural insights and offer new opportunities for the drug discovery of better selective pharmaceuticals targeting specific SSTR subtypes. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_39931.map.gz | 28.7 MB | EMDB map data format | |
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Header (meta data) | emd-39931-v30.xml emd-39931.xml | 19.3 KB 19.3 KB | Display Display | EMDB header |
Images | emd_39931.png | 52.1 KB | ||
Filedesc metadata | emd-39931.cif.gz | 6.9 KB | ||
Others | emd_39931_half_map_1.map.gz emd_39931_half_map_2.map.gz | 28.2 MB 28.2 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-39931 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-39931 | HTTPS FTP |
-Validation report
Summary document | emd_39931_validation.pdf.gz | 752.9 KB | Display | EMDB validaton report |
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Full document | emd_39931_full_validation.pdf.gz | 752.5 KB | Display | |
Data in XML | emd_39931_validation.xml.gz | 10.7 KB | Display | |
Data in CIF | emd_39931_validation.cif.gz | 12.4 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-39931 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-39931 | HTTPS FTP |
-Related structure data
Related structure data | 8zcjMC 8zbeC 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_39931.map.gz / Format: CCP4 / Size: 30.5 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: 1.07 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_39931_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_39931_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : pasireotide-SSTR5-Gi complex
Entire | Name: pasireotide-SSTR5-Gi complex |
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Components |
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-Supramolecule #1: pasireotide-SSTR5-Gi complex
Supramolecule | Name: pasireotide-SSTR5-Gi complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Guanine nucleotide-binding protein G(i) subunit alpha-1
Macromolecule | Name: Guanine nucleotide-binding protein G(i) subunit alpha-1 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: 40.445059 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVGAQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHESM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCS TDTKNVQFVF DAVTDVIIKN NLKDCGLF UniProtKB: 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 | 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: Rattus norvegicus (Norway rat) |
Molecular weight | Theoretical: 41.055867 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MHHHHHHGSL LQSELDQLRQ EAEQLKNQIR DARKACADAT LSQITNNIDP VGRIQMRTRR TLRGHLAKIY AMHWGTDSRL LVSASQDGK LIIWDSYTTN KVHAIPLRSS WVMTCAYAPS GNYVACGGLD NICSIYNLKT REGNVRVSRE LAGHTGYLSC C RFLDDNQI ...String: MHHHHHHGSL LQSELDQLRQ EAEQLKNQIR DARKACADAT LSQITNNIDP VGRIQMRTRR TLRGHLAKIY AMHWGTDSRL LVSASQDGK LIIWDSYTTN KVHAIPLRSS WVMTCAYAPS GNYVACGGLD NICSIYNLKT REGNVRVSRE LAGHTGYLSC C RFLDDNQI VTSSGDTTCA LWDIETGQQT TTFTGHTGDV MSLSLAPDTR LFVSGACDAS AKLWDVREGM CRQTFTGHES DI NAICFFP NGNAFATGSD DATCRLFDLR ADQELMTYSH DNIICGITSV SFSKSGRLLL AGYDDFNCNV WDALKADRAG VLA GHDNRV SCLGVTDDGM AVATGSWDSF LKIWNGSSGG GGSGGGGSSG VSGWRLFKKI S 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: Bos taurus (cattle) |
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: ScFv16
Macromolecule | Name: ScFv16 / 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: 32.724473 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MLLVNQSHQG FNKEHTSKMV SAIVLYVLLA AAAHSAFAVQ LVESGGGLVQ PGGSRKLSCS ASGFAFSSFG MHWVRQAPEK GLEWVAYIS SGSGTIYYAD TVKGRFTISR DDPKNTLFLQ MTSLRSEDTA MYYCVRSIYY YGSSPFDFWG QGTTLTVSSG G GGSGGGGS ...String: MLLVNQSHQG FNKEHTSKMV SAIVLYVLLA AAAHSAFAVQ LVESGGGLVQ PGGSRKLSCS ASGFAFSSFG MHWVRQAPEK GLEWVAYIS SGSGTIYYAD TVKGRFTISR DDPKNTLFLQ MTSLRSEDTA MYYCVRSIYY YGSSPFDFWG QGTTLTVSSG G GGSGGGGS GGGGSSDIVM TQATSSVPVT PGESVSISCR SSKSLLHSNG NTYLYWFLQR PGQSPQLLIY RMSNLASGVP DR FSGSGSG TAFTLTISRL EAEDVGVYYC MQHLEYPLTF GAGTKLELVD ENLYFQGASH HHHHHHH |
-Macromolecule #5: Beta-2 adrenergic receptor,Somatostatin receptor type 5,lgbit (fu...
Macromolecule | Name: Beta-2 adrenergic receptor,Somatostatin receptor type 5,lgbit (fusion protein) type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Oplophorus gracilirostris (crustacean) |
Molecular weight | Theoretical: 62.01593 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MKTIIALSYI FCLVFADYKD DDDKMGQPGN GSAFLLAPNG SHAPDHDVME PLFPASTPSW NASSPGAASG GGDNRTLVGP APSAGARAV LVPVLYLLVC AAGLGGNTLV IYVVLRFAKM KTVTNIYILN LAVADVLYML GLPFLATQNA ASFWPFGPVL C RLVMTLDG ...String: MKTIIALSYI FCLVFADYKD DDDKMGQPGN GSAFLLAPNG SHAPDHDVME PLFPASTPSW NASSPGAASG GGDNRTLVGP APSAGARAV LVPVLYLLVC AAGLGGNTLV IYVVLRFAKM KTVTNIYILN LAVADVLYML GLPFLATQNA ASFWPFGPVL C RLVMTLDG VNQFTSVFCL TVMSVDRYLA VVHPLSSARW RRPRVAKLAS AAAWVLSLCM SLPLLVFADV QEGGTCNASW PE PVGLWGA VFIIYTAVLG FFAPLLVICL CYLLIVVKVR AAGVRVGCVR RRSERKVTRM VLVVVLVFAG CWLPFFTVNI VNL AVALPQ EPASAGLYFF VVILSYANSC ANPVLYGFLS DNFRQSFQKV LCLRKGSGAK DADATEPRPD RIRQQQEATP PAHR AAANG LMQTSKLVFT LEDFVGDWEQ TAAYNLDQVL EQGGVSSLLQ NLAVSVTPIQ RIVRSGENAL KIDIHVIIPY EGLSA DQMA QIEEVFKVVY PVDDHHFKVI LPYGTLVIDG VTPNMLNYFG RPYEGIAVFD GKKITVTGTL WNGNKIIDER LITPDG SML FRVTINS UniProtKB: Beta-2 adrenergic receptor, Somatostatin receptor type 5 |
-Macromolecule #6: 004-DTR-LYS-TYR-PHA-HYP
Macromolecule | Name: 004-DTR-LYS-TYR-PHA-HYP / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: synthetic construct (others) |
Molecular weight | Theoretical: 874.016 Da |
Sequence | String: (004)(DTR)KY(PHA)(HYP) |
-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: GATAN K3 (6k x 4k) / Average electron dose: 55.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: SPOT SCAN / Imaging mode: DIFFRACTION / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.4000000000000001 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: 3.09 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1227503 |
Initial angle assignment | Type: ANGULAR RECONSTITUTION |
Final angle assignment | Type: ANGULAR RECONSTITUTION |