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- PDB-8zbe: cryo-EM structure of the octreotide-bound SSTR5-Gi complex -

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Basic information

Entry
Database: PDB / ID: 8zbe
Titlecryo-EM structure of the octreotide-bound SSTR5-Gi complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Beta-2 adrenergic receptor,Somatostatin receptor type 5,lgbit (fusion protein)
  • ScFv16
  • octreotide
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / SSTR5 / octreoitde / structural protein / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


somatostatin receptor activity / beta2-adrenergic 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 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding ...somatostatin receptor activity / beta2-adrenergic 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 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / positive regulation of mini excitatory postsynaptic potential / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / G alpha (z) signalling events / AMPA selective glutamate receptor signaling pathway / heat generation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure / adenylate cyclase-inhibiting adrenergic receptor signaling pathway / positive regulation of autophagosome maturation / norepinephrine binding / Vasopressin regulates renal water homeostasis via Aquaporins / Adrenoceptors / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / negative regulation of smooth muscle contraction / G alpha (q) signalling events / positive regulation of cardiac muscle cell contraction / positive regulation of lipophagy / negative regulation of multicellular organism growth / G alpha (i) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / neuropeptide binding / cellular response to glucocorticoid stimulus / negative regulation of G protein-coupled receptor signaling pathway / smooth muscle contraction / adrenergic receptor signaling pathway / photoreceptor outer segment membrane / spectrin binding / response to psychosocial stress / diet induced thermogenesis / endosome to lysosome transport / positive regulation of cytokinesis / alkylglycerophosphoethanolamine phosphodiesterase activity / regulation of insulin secretion / positive regulation of cAMP/PKA signal transduction / negative regulation of cardiac muscle cell apoptotic process / adenylate cyclase binding / bone resorption / potassium channel regulator activity / positive regulation of bone mineralization / photoreceptor outer segment / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / neuronal dense core vesicle / regulation of sodium ion transport / intercellular bridge / adenylate cyclase-activating adrenergic receptor signaling pathway / regulation of eating behavior / cardiac muscle cell apoptotic process / adenylate cyclase inhibitor activity / photoreceptor inner segment / positive regulation of protein localization to cell cortex / T cell migration / positive regulation of relaxation of smooth muscle / positive regulation of cardiac muscle cell apoptotic process / Adenylate cyclase inhibitory pathway / D2 dopamine receptor binding / receptor-mediated endocytosis / adenylate cyclase-inhibiting serotonin receptor signaling pathway / brown fat cell differentiation / G protein-coupled serotonin receptor binding / response to cold / cellular response to forskolin / mast cell degranulation / Peptide ligand-binding receptors / regulation of mitotic spindle organization / chemokine-mediated signaling pathway / clathrin-coated endocytic vesicle membrane / Regulation of insulin secretion / neuropeptide signaling pathway / response to prostaglandin E / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor binding / response to peptide hormone / cellular response to amyloid-beta / G-protein beta/gamma-subunit complex binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / mitotic spindle / GDP binding / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / glucose homeostasis / G alpha (z) signalling events / ADORA2B mediated anti-inflammatory cytokines production / Cargo recognition for clathrin-mediated endocytosis / positive regulation of cold-induced thermogenesis / amyloid-beta binding
Similarity search - Function
Somatostatin receptor 5 / Somatostatin receptor family / Beta 2 adrenoceptor / Adrenoceptor family / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit ...Somatostatin receptor 5 / Somatostatin receptor family / Beta 2 adrenoceptor / Adrenoceptor family / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Guanine nucleotide-binding protein subunit gamma / Beta-2 adrenergic receptor / Somatostatin receptor type 5 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(i) subunit alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Oplophorus gracilirostris (arthropod)
Rattus norvegicus (Norway rat)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.24 Å
AuthorsLi, Y.G. / Meng, X.Y. / Yang, X.R. / Ling, S.L. / Shi, P. / Tian, C.L. / Yang, F.
Funding support1items
OrganizationGrant numberCountry
Other government
CitationJournal: 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
DepositionApr 26, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jul 10, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2024Group: Data collection / Database references / Structure summary
Category: citation / em_admin ...citation / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.2Nov 13, 2024Group: Data collection / Category: em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Beta-2 adrenergic receptor,Somatostatin receptor type 5,lgbit (fusion protein)
B: Guanine nucleotide-binding protein G(i) subunit alpha-1
D: Guanine nucleotide-binding protein subunit gamma
E: ScFv16
P: octreotide
C: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1


Theoretical massNumber of molelcules
Total (without water)185,1236
Polymers185,1236
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules BDC

#2: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40445.059 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63096
#3: Protein Guanine nucleotide-binding protein subunit gamma / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: A0A9X9ZA26
#6: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 41055.867 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Gnb1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P54311

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Protein / Antibody / Protein/peptide , 3 types, 3 molecules AEP

#1: Protein Beta-2 adrenergic receptor,Somatostatin receptor type 5,lgbit (fusion protein) / Beta-2 adrenoreceptor / Beta-2 adrenoceptor / SS-5-R / SS5-R / SS5R / SST5


Mass: 62015.930 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Oplophorus gracilirostris (arthropod)
Gene: ADRB2, ADRB2R, B2AR, SSTR5 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P07550, UniProt: P35346
#4: Antibody ScFv16


Mass: 32708.473 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)
#5: Protein/peptide octreotide


Mass: 1036.246 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: octreotide-bound SSTR5-Gi complex / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
31Bos taurus (domestic cattle)9913
41Rattus norvegicus (Norway rat)10116
51Oplophorus gracilirostris (arthropod)727944
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: DIFFRACTION / Nominal defocus max: 2000 nm / Nominal defocus min: 1400 nm
Image recordingElectron dose: 55 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487: / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.24 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 452725 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0078000
ELECTRON MICROSCOPYf_angle_d1.01310924
ELECTRON MICROSCOPYf_dihedral_angle_d4.5251172
ELECTRON MICROSCOPYf_chiral_restr0.0421304
ELECTRON MICROSCOPYf_plane_restr0.0041415

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