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- PDB-7d3s: Human SECR in complex with an engineered Gs heterotrimer -

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Basic information

Entry
Database: PDB / ID: 7d3s
TitleHuman SECR in complex with an engineered Gs heterotrimer
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Secretin
  • Secretin receptor
  • nanobody Nb35
KeywordsMEMBRANE PROTEIN / CLASS B GPCR / Secretin / SECR / SIGNALING PROTEIN-HORMONE COMPLEX
Function / homology
Function and homology information


secretin receptor activity / digestive hormone activity / positive regulation of somatostatin secretion / negative regulation of gastrin-induced gastric acid secretion / positive regulation of pancreatic juice secretion / regulation of appetite / pancreatic juice secretion / intracellular water homeostasis / positive regulation of lipid catabolic process / positive regulation of cAMP-mediated signaling ...secretin receptor activity / digestive hormone activity / positive regulation of somatostatin secretion / negative regulation of gastrin-induced gastric acid secretion / positive regulation of pancreatic juice secretion / regulation of appetite / pancreatic juice secretion / intracellular water homeostasis / positive regulation of lipid catabolic process / positive regulation of cAMP-mediated signaling / embryonic digestive tract development / 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 / G protein-coupled peptide receptor activity / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / 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 / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (i) signalling events / 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 / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / alkylglycerophosphoethanolamine phosphodiesterase activity / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / G alpha (q) signalling events / photoreceptor outer segment membrane / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / spectrin binding / Vasopressin regulates renal water homeostasis via Aquaporins / cytoplasmic microtubule / diet induced thermogenesis / peptide hormone binding / PKA activation in glucagon signalling / hair follicle placode formation / photoreceptor outer segment / developmental growth / D1 dopamine receptor binding / intracellular transport / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / cardiac muscle cell apoptotic process / adenylate cyclase activator activity / photoreceptor inner segment / response to nutrient levels / trans-Golgi network membrane / G protein-coupled receptor binding / hippocampus development / G-protein beta/gamma-subunit complex binding / bone development / brain development / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / regulation of synaptic plasticity / adenylate cyclase-activating G protein-coupled receptor signaling pathway / hormone activity / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / cognition / platelet aggregation / 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 / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / GPER1 signaling / G-protein beta-subunit binding
Similarity search - Function
GPCR, family 2, secretin receptor / Secretin precursor / : / Glucagon/GIP/secretin/VIP / Peptide hormone / Glucagon / GIP / secretin / VIP family signature. / Glucagon like hormones / : / G-protein coupled receptors family 2 signature 1. / Hormone receptor domain ...GPCR, family 2, secretin receptor / Secretin precursor / : / Glucagon/GIP/secretin/VIP / Peptide hormone / Glucagon / GIP / secretin / VIP family signature. / Glucagon like hormones / : / G-protein coupled receptors family 2 signature 1. / Hormone receptor domain / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / GPCR family 2, extracellular hormone receptor domain superfamily / G-protein coupled receptors family 2 signature 2. / GPCR, family 2, secretin-like, conserved site / GPCR, family 2, secretin-like / 7 transmembrane receptor (Secretin family) / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2. / G-protein alpha subunit, group S / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / 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. / WD domain, G-beta repeat / 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
Secretin / Secretin receptor / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Rattus norvegicus (Norway rat)
Bos taurus (cattle)
unidentified (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsFukuhara, S. / Kobayashi, K. / Kusakizako, T. / Shihoya, W. / Nureki, O.
CitationJournal: Biochem Biophys Res Commun / Year: 2020
Title: Structure of the human secretin receptor coupled to an engineered heterotrimeric G protein.
Authors: Satoshi Fukuhara / Kazuhiro Kobayashi / Tsukasa Kusakizako / Wataru Iida / Masahiko Kato / Wataru Shihoya / Osamu Nureki /
Abstract: Secretin is a gastrointestinal hormone that exerts multiple physiological functions via activation of the secretin receptor (SECR). SECR belongs to the class B G-protein-coupled receptors and is ...Secretin is a gastrointestinal hormone that exerts multiple physiological functions via activation of the secretin receptor (SECR). SECR belongs to the class B G-protein-coupled receptors and is involved in various processes, such as regulation of the pH of the duodenal content, food intake, and water homeostasis. Here, we report a cryo-electron microscopy structure of human SECR bound to secretin and an engineered Gs heterotrimer. The structure revealed the basic architecture of SECR and the secretin binding mode. A structural comparison of the SECR and PAC1R transmembrane domains revealed that transmembrane helices 1 and 2 play a prominent role in secretin recognition. Moreover, the extracellular domain of SECR is perpendicular to the TMD, unlike that of PAC1R. This comparison revealed the diverged peptide recognition mechanisms of these receptors, which belong to the same subgroup. Our structural information will facilitate drug discovery research for clinical applications.
History
DepositionSep 20, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 4, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 30, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

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Assembly

Deposited unit
P: Secretin
R: Secretin receptor
A: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
N: nanobody Nb35


Theoretical massNumber of molelcules
Total (without water)158,3516
Polymers158,3516
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area14100 Å2
ΔGint-73 kcal/mol
Surface area45770 Å2

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Components

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

#3: Protein Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Adenylate cyclase-stimulating G alpha protein


Mass: 44255.664 Da / Num. of mol.: 1
Mutation: deletion 254-263, G49D,E50N,L63Y,A249D,S252D,I375A,V375I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS, GNAS1, GSP / Production host: Escherichia coli (E. coli) / References: UniProt: P63092
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 38744.371 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
#5: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7547.685 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63212

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

#1: Protein/peptide Secretin


Mass: 3045.436 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P09683
#2: Protein Secretin receptor / SCT-R


Mass: 49742.422 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SCTR / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P47872
#6: Antibody nanobody Nb35


Mass: 15015.728 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) unidentified (others) / Production host: Escherichia coli (E. coli)

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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

Component
IDNameTypeEntity IDParent-IDSource
1SECR-Gs complexCOMPLEXall0RECOMBINANT
2SecretinCOMPLEX#11RECOMBINANT
3Secretin receptorCOMPLEX#21RECOMBINANT
4Guanine nucleotide-binding protein G(s) subunit alpha isoforms shortCOMPLEX#31RECOMBINANT
5Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1COMPLEX#41RECOMBINANT
6Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2COMPLEX#51RECOMBINANT
7nanobody Nb35COMPLEX#61RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
32Homo sapiens (human)9606
43Homo sapiens (human)9606
55Rattus norvegicus (Norway rat)10116
66Bos taurus (cattle)9913
77unidefined (others)32644
Buffer solutionpH: 8
SpecimenConc.: 5.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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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: OTHER
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 50.8 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of real images: 2142

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Processing

EM softwareName: PHENIX / Version: 1.14 / Category: model refinement / Details: phenix.real_space_refine
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 617465 / Symmetry type: POINT
Atomic model buildingProtocol: OTHER
Atomic model buildingPDB-ID: 5VAI

5vai

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