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- PDB-8g59: Cryo-EM structure of the TUG891 bound GPR120-Giq complex -

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Basic information

Entry
Database: PDB / ID: 8g59
TitleCryo-EM structure of the TUG891 bound GPR120-Giq complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Free fatty acid receptor 4
  • scFv16
KeywordsMEMBRANE PROTEIN / GPCR / GPR120 / complex / fatty acid hormones
Function / homology
Function and homology information


negative regulation of somatostatin secretion / ghrelin secretion / positive regulation of glucagon secretion / taste receptor activity / Free fatty acid receptors / regulation of glucose transmembrane transport / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / PLC beta mediated events / phospholipase C-activating dopamine receptor signaling pathway ...negative regulation of somatostatin secretion / ghrelin secretion / positive regulation of glucagon secretion / taste receptor activity / Free fatty acid receptors / regulation of glucose transmembrane transport / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / PLC beta mediated events / phospholipase C-activating dopamine receptor signaling pathway / entrainment of circadian clock / regulation of platelet activation / hormone secretion / phototransduction, visible light / arrestin family protein binding / glutamate receptor signaling pathway / regulation of canonical Wnt signaling pathway / negative regulation of cytokine production / ciliary membrane / negative regulation of interleukin-1 beta production / action potential / activation of phospholipase C activity / endocytic vesicle / white fat cell differentiation / photoreceptor outer segment / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / positive regulation of osteoblast differentiation / G protein-coupled serotonin receptor binding / positive regulation of cAMP-mediated signaling / brown fat cell differentiation / regulation of mitotic spindle organization / cellular response to forskolin / cellular response to hormone stimulus / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / positive regulation of brown fat cell differentiation / GTPase activator activity / Regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / fatty acid binding / peptide binding / negative regulation of protein kinase activity / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / cilium / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Sensory perception of sweet, bitter, and umami (glutamate) taste / response to peptide hormone / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / negative regulation of inflammatory response / 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 / adenylate cyclase-activating dopamine receptor signaling pathway / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / sensory perception of taste / GPER1 signaling / GDP binding / G-protein beta-subunit binding / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / G alpha (12/13) signalling events / signaling receptor complex adaptor activity / blood coagulation / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / GTPase binding / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cold-induced thermogenesis / cell cortex / midbody / positive regulation of cytosolic calcium ion concentration / G alpha (i) signalling events
Similarity search - Function
G-protein alpha subunit, group Q / G-protein alpha subunit, group I / 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 alpha subunit, group Q / G-protein alpha subunit, group I / 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-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-YN9 / Guanine nucleotide-binding protein G(q) subunit alpha / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(i) subunit alpha-1 / Free fatty acid receptor 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.64 Å
AuthorsMao, C. / Xiao, P. / Tao, X. / Qin, J. / He, Q. / Zhang, C. / Yu, X. / Zhang, Y. / Sun, J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Science / Year: 2023
Title: Unsaturated bond recognition leads to biased signal in a fatty acid receptor.
Authors: Chunyou Mao / Peng Xiao / Xiao-Na Tao / Jiao Qin / Qing-Tao He / Chao Zhang / Sheng-Chao Guo / Ya-Qin Du / Li-Nan Chen / Dan-Dan Shen / Zhi-Shuai Yang / Han-Qiong Zhang / Shen-Ming Huang / ...Authors: Chunyou Mao / Peng Xiao / Xiao-Na Tao / Jiao Qin / Qing-Tao He / Chao Zhang / Sheng-Chao Guo / Ya-Qin Du / Li-Nan Chen / Dan-Dan Shen / Zhi-Shuai Yang / Han-Qiong Zhang / Shen-Ming Huang / Yong-Hao He / Jie Cheng / Ya-Ni Zhong / Pan Shang / Jun Chen / Dao-Lai Zhang / Qian-Lang Wang / Mei-Xia Liu / Guo-Yu Li / Yongyuan Guo / H Eric Xu / Chuanxin Wang / Cheng Zhang / Shiqing Feng / Xiao Yu / Yan Zhang / Jin-Peng Sun /
Abstract: Individual free fatty acids (FAs) play important roles in metabolic homeostasis, many through engagement with more than 40G protein-coupled receptors. Searching for receptors to sense beneficial ...Individual free fatty acids (FAs) play important roles in metabolic homeostasis, many through engagement with more than 40G protein-coupled receptors. Searching for receptors to sense beneficial omega-3 FAs of fish oil enabled the identification of GPR120, which is involved in a spectrum of metabolic diseases. Here, we report six cryo-electron microscopy structures of GPR120 in complex with FA hormones or TUG891 and G or G trimers. Aromatic residues inside the GPR120 ligand pocket were responsible for recognizing different double-bond positions of these FAs and connect ligand recognition to distinct effector coupling. We also investigated synthetic ligand selectivity and the structural basis of missense single-nucleotide polymorphisms. We reveal how GPR120 differentiates rigid double bonds and flexible single bonds. The knowledge gleaned here may facilitate rational drug design targeting to GPR120.
History
DepositionFeb 12, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 8, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 15, 2023Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Apr 19, 2023Group: Database references / Category: citation / Item: _citation.journal_volume

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Y: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
S: scFv16
A: Guanine nucleotide-binding protein G(q) subunit alpha
R: Free fatty acid receptor 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)156,9636
Polymers156,5985
Non-polymers3641
Water0
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 BYA

#1: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37285.734 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#2: 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.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768
#4: Protein Guanine nucleotide-binding protein G(q) subunit alpha / Adenylate cyclase-inhibiting G alpha protein / Guanine nucleotide-binding protein alpha-q


Mass: 40555.199 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1, GNAQ, GAQ / Variant: G203A A326S / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63096, UniProt: P50148

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Antibody / Protein / Non-polymers , 3 types, 3 molecules SR

#3: Antibody scFv16


Mass: 30363.043 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 Free fatty acid receptor 4 / G-protein coupled receptor 120 / G-protein coupled receptor 129 / G-protein coupled receptor GT01 / ...G-protein coupled receptor 120 / G-protein coupled receptor 129 / G-protein coupled receptor GT01 / G-protein coupled receptor PGR4 / Omega-3 fatty acid receptor 1


Mass: 40533.211 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FFAR4, GPR120, GPR129, O3FAR1, PGR4 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q5NUL3
#6: Chemical ChemComp-YN9 / 3-{4-[(4-fluoro-4'-methyl[1,1'-biphenyl]-2-yl)methoxy]phenyl}propanoic acid


Mass: 364.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H21FO3 / 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 TUG891 bound GPR120-Giq complex
Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
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: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 52 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.64 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 303739 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0058780
ELECTRON MICROSCOPYf_angle_d0.71311934
ELECTRON MICROSCOPYf_dihedral_angle_d12.3253038
ELECTRON MICROSCOPYf_chiral_restr0.0531395
ELECTRON MICROSCOPYf_plane_restr0.0061495

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