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- PDB-7dty: Structural basis of ligand selectivity conferred by the human glu... -

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Basic information

Entry
Database: PDB / ID: 7dty
TitleStructural basis of ligand selectivity conferred by the human glucose-dependent insulinotropic polypeptide receptor
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Gastric inhibitory polypeptide
  • Nanobody-35
  • human glucose-dependent insulinotropic polypeptide receptor
KeywordsSTRUCTURAL PROTEIN / Glucose-dependent insulinotropic polypeptide receptor / cryo-electron microscopy / G protein-coupled receptor / ligand recognition
Function / homology
Function and homology information


gastric inhibitory polypeptide receptor binding / digestive system development / gastric inhibitory peptide signaling pathway / glucagon receptor binding / regulation of fatty acid biosynthetic process / positive regulation of cAMP-mediated signaling / Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) / sensory perception of chemical stimulus / endocrine pancreas development / response to selenium ion ...gastric inhibitory polypeptide receptor binding / digestive system development / gastric inhibitory peptide signaling pathway / glucagon receptor binding / regulation of fatty acid biosynthetic process / positive regulation of cAMP-mediated signaling / Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) / sensory perception of chemical stimulus / endocrine pancreas development / response to selenium ion / 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 / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / G alpha (z) signalling events / response to acidic pH / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / positive regulation of glucose transmembrane transport / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / triglyceride homeostasis / G alpha (i) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / 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 / alkylglycerophosphoethanolamine phosphodiesterase activity / ADP signalling through P2Y purinoceptor 12 / 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 / exploration behavior / 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 / response to lipid / response to starvation / regulation of insulin secretion / mu-type opioid receptor binding / photoreceptor outer segment / corticotropin-releasing hormone receptor 1 binding / response to axon injury / D1 dopamine receptor binding / response to amino acid / response to glucose / beta-2 adrenergic receptor binding / adenylate cyclase-activating adrenergic receptor signaling pathway / sensory perception of pain / cardiac muscle cell apoptotic process / adenylate cyclase activator activity / photoreceptor inner segment / adult locomotory behavior / female pregnancy / long-term synaptic potentiation / ionotropic glutamate receptor binding / insulin-like growth factor receptor binding / G-protein beta/gamma-subunit complex binding / adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of insulin secretion / response to organic cyclic compound / hormone activity / memory / response to peptide hormone / Glucagon-type ligand receptors / cellular response to catecholamine stimulus / sensory perception of taste / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / signaling receptor complex adaptor activity / GTPase binding / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway
Similarity search - Function
Gastric inhibitory polypeptide / Glucagon/GIP/secretin/VIP / Peptide hormone / Glucagon / GIP / secretin / VIP family signature. / Glucagon like hormones / 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 ...Gastric inhibitory polypeptide / Glucagon/GIP/secretin/VIP / Peptide hormone / Glucagon / GIP / secretin / VIP family signature. / Glucagon like hormones / 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
CHOLESTEROL / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Gastric inhibitory polypeptide / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Bos taurus (cattle)
Rattus norvegicus (Norway rat)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.98 Å
AuthorsZhao, F.H. / Zhang, C. / Zhou, Q.T. / Hang, K.N. / Zou, X.Y. / Chen, Y. / Wu, F. / Rao, Q.D. / Dai, A.T. / Yin, W.C. ...Zhao, F.H. / Zhang, C. / Zhou, Q.T. / Hang, K.N. / Zou, X.Y. / Chen, Y. / Wu, F. / Rao, Q.D. / Dai, A.T. / Yin, W.C. / Shen, D.D. / Zhang, Y. / Xia, T. / Stevens, R.C. / Xu, H.E. / Yang, D.H. / Zhao, L.H. / Wang, M.W.
Funding support China, 4items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81872915 China
National Natural Science Foundation of China (NSFC)21704064 China
National Natural Science Foundation of China (NSFC)81773792 China
National Natural Science Foundation of China (NSFC)32071203 China
CitationJournal: Elife / Year: 2021
Title: Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor.
Authors: Fenghui Zhao / Chao Zhang / Qingtong Zhou / Kaini Hang / Xinyu Zou / Yan Chen / Fan Wu / Qidi Rao / Antao Dai / Wanchao Yin / Dan-Dan Shen / Yan Zhang / Tian Xia / Raymond C Stevens / H Eric ...Authors: Fenghui Zhao / Chao Zhang / Qingtong Zhou / Kaini Hang / Xinyu Zou / Yan Chen / Fan Wu / Qidi Rao / Antao Dai / Wanchao Yin / Dan-Dan Shen / Yan Zhang / Tian Xia / Raymond C Stevens / H Eric Xu / Dehua Yang / Lihua Zhao / Ming-Wei Wang /
Abstract: Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone that exerts crucial metabolic functions by binding and activating its cognate receptor, GIPR. As an important therapeutic ...Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone that exerts crucial metabolic functions by binding and activating its cognate receptor, GIPR. As an important therapeutic target, GIPR has been subjected to intensive structural studies without success. Here, we report the cryo-EM structure of the human GIPR in complex with GIP and a G heterotrimer at a global resolution of 2.9 Å. GIP adopts a single straight helix with its N terminus dipped into the receptor transmembrane domain (TMD), while the C terminus is closely associated with the extracellular domain and extracellular loop 1. GIPR employs conserved residues in the lower half of the TMD pocket to recognize the common segments shared by GIP homologous peptides, while uses non-conserved residues in the upper half of the TMD pocket to interact with residues specific for GIP. These results provide a structural framework of hormone recognition and GIPR activation.
History
DepositionJan 6, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 4, 2021Provider: repository / Type: Initial release
Revision 1.1Aug 11, 2021Group: Database references / Category: citation_author / database_2
Item: _citation_author.identifier_ORCID / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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Assembly

Deposited unit
R: human glucose-dependent insulinotropic polypeptide receptor
P: Gastric inhibitory polypeptide
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-35
hetero molecules


Theoretical massNumber of molelcules
Total (without water)181,42012
Polymers179,1006
Non-polymers2,3206
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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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: 45727.441 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Gene: GNAS, GNAS1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P04896
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 40226.992 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: 7861.143 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 / Protein/peptide / Antibody / Non-polymers , 4 types, 9 molecules RPN

#1: Protein human glucose-dependent insulinotropic polypeptide receptor


Mass: 64950.695 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: mutations:1 / Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)
#2: Protein/peptide Gastric inhibitory polypeptide / GIP / Glucose-dependent insulinotropic polypeptide / Incretin hormone


Mass: 4990.586 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P09681
#6: Antibody Nanobody-35


Mass: 15343.019 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)
#7: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C27H46O / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY

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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: Cryo-EM structure of the human glucose-dependent insulinotropic polypeptide receptor in complex with GIP and G protein
Type: COMPLEX / Entity ID: #1-#6 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
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: OTHER / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 80 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.13_2998: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.98 Å / Resolution method: DIFFRACTION PATTERN/LAYERLINES / Num. of particles: 295021 / Symmetry type: POINT

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