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- PDB-8yk0: Cryo-EM structure of human GPR156-Gi3 complex -

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Basic information

Entry
Database: PDB / ID: 8yk0
TitleCryo-EM structure of human GPR156-Gi3 complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • (Probable G-protein coupled receptor ...) x 2
KeywordsMEMBRANE PROTEIN / GPCR / class C / GPR156 / cryo-EM / homodimer / active state
Function / homology
Function and homology information


stereocilium bundle organization / G protein-coupled GABA receptor activity / G protein-coupled receptor heterodimeric complex / negative regulation of adenylate cyclase 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 ...stereocilium bundle organization / G protein-coupled GABA receptor activity / G protein-coupled receptor heterodimeric complex / negative regulation of adenylate cyclase 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 / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / G alpha (z) signalling events / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / GTP metabolic process / 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 / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (12/13) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Ca2+ pathway / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / photoreceptor outer segment membrane / G alpha (q) signalling events / gamma-aminobutyric acid signaling pathway / G alpha (i) signalling events / spectrin binding / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / alkylglycerophosphoethanolamine phosphodiesterase activity / positive regulation of macroautophagy / photoreceptor outer segment / Adenylate cyclase inhibitory pathway / photoreceptor inner segment / cardiac muscle cell apoptotic process / G protein-coupled receptor binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / centriolar satellite / ADP signalling through P2Y purinoceptor 12 / GDP binding / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / sensory perception of taste / signaling receptor complex adaptor activity / cell body / GTPase binding / positive regulation of cytosolic calcium ion concentration / retina development in camera-type eye / midbody / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / cellular response to hypoxia / Extra-nuclear estrogen signaling / cell population proliferation / ciliary basal body / G protein-coupled receptor signaling pathway / lysosomal membrane / cell division / GTPase activity / synapse / centrosome / dendrite / protein-containing complex binding / GTP binding / nucleolus / Golgi apparatus
Similarity search - Function
GPR156, 7TM domain / GPCR family 3, GABA-B receptor / G-protein coupled receptors family 3 profile. / GPCR family 3, C-terminal / 7 transmembrane sweet-taste receptor of 3 GCPR / G-protein alpha subunit, group I / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. ...GPR156, 7TM domain / GPCR family 3, GABA-B receptor / G-protein coupled receptors family 3 profile. / GPCR family 3, C-terminal / 7 transmembrane sweet-taste receptor of 3 GCPR / G-protein alpha subunit, group I / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / 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 / 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. / WD domain, G-beta repeat / 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
CHOLESTEROL / Chem-MW9 / Guanine nucleotide-binding protein G(i) subunit alpha-3 / 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 / Probable G-protein coupled receptor 156
Similarity search - Component
Biological speciesHomo sapiens (human)
Rattus norvegicus (Norway rat)
Bos taurus (domestic cattle)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.4 Å
AuthorsMa, X.Y. / Chen, L.N. / Liao, M.H. / Zhang, L.Y. / Xi, K. / Guo, J.M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2024
Title: Molecular insights into the activation mechanism of GPR156 in maintaining auditory function.
Authors: Xiangyu Ma / Li-Nan Chen / Menghui Liao / Liyan Zhang / Kun Xi / Jiamin Guo / Cangsong Shen / Dan-Dan Shen / Pengjun Cai / Qingya Shen / Jieyu Qi / Huibing Zhang / Shao-Kun Zang / Ying-Jun ...Authors: Xiangyu Ma / Li-Nan Chen / Menghui Liao / Liyan Zhang / Kun Xi / Jiamin Guo / Cangsong Shen / Dan-Dan Shen / Pengjun Cai / Qingya Shen / Jieyu Qi / Huibing Zhang / Shao-Kun Zang / Ying-Jun Dong / Luwei Miao / Jiao Qin / Su-Yu Ji / Yue Li / Jianfeng Liu / Chunyou Mao / Yan Zhang / Renjie Chai /
Abstract: The class C orphan G-protein-coupled receptor (GPCR) GPR156, which lacks the large extracellular region, plays a pivotal role in auditory function through G. Here, we firstly demonstrate that GPR156 ...The class C orphan G-protein-coupled receptor (GPCR) GPR156, which lacks the large extracellular region, plays a pivotal role in auditory function through G. Here, we firstly demonstrate that GPR156 with high constitutive activity is essential for maintaining auditory function, and further reveal the structural basis of the sustained role of GPR156. We present the cryo-EM structures of human apo GPR156 and the GPR156-G complex, unveiling a small extracellular region formed by extracellular loop 2 (ECL2) and the N-terminus. The GPR156 dimer in both apo state and G protein-coupled state adopt a transmembrane (TM)5/6-TM5/6 interface, indicating the high constitutive activity of GPR156 in the apo state. Furthermore, C-terminus in G-bound subunit of GPR156 plays a dual role in promoting G protein binding within G-bound subunit while preventing the G-free subunit from binding to additional G protein. Together, these results explain how GPR156 constitutive activity is maintained through dimerization and provide a mechanistic insight into the sustained role of GPR156 in maintaining auditory function.
History
DepositionMar 3, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Feb 5, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Probable G-protein coupled receptor 156
D: 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
C: Guanine nucleotide-binding protein G(i) subunit alpha-3
A: Probable G-protein coupled receptor 156
hetero molecules


Theoretical massNumber of molelcules
Total (without water)158,80920
Polymers151,4475
Non-polymers7,36115
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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Probable G-protein coupled receptor ... , 2 types, 2 molecules BA

#1: Protein Probable G-protein coupled receptor 156 / G-protein coupled receptor PGR28 / GABAB-related G-protein coupled receptor


Mass: 32797.066 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GPR156, GABABL, PGR28 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8NFN8
#5: Protein Probable G-protein coupled receptor 156 / G-protein coupled receptor PGR28 / GABAB-related G-protein coupled receptor


Mass: 35083.629 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GPR156, GABABL, PGR28 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8NFN8

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

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


Mass: 37198.656 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
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 6289.240 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63212
#4: Protein Guanine nucleotide-binding protein G(i) subunit alpha-3 / G(i) alpha-3


Mass: 40078.512 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI3 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P08754

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Non-polymers , 2 types, 15 molecules

#6: Chemical
ChemComp-MW9 / (21R,24R,27S)-24,27,28-trihydroxy-18,24-dioxo-19,23,25-trioxa-24lambda~5~-phosphaoctacosan-21-yl (9Z)-octadec-9-enoate / 1-stearoyl-2-oleoyl-sn-glycero-3-phospho-(1'-rac-glycerol)


Mass: 777.060 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C42H81O10P
#7: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: C27H46O

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Details

Has ligand of interestN
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: GPR156-Gi3 complex / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1-#4 / Source: RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Homo sapiens (human)9606
21Bos taurus (domestic cattle)9913
31Rattus norvegicus (Norway rat)10116
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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 700 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 52 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1153971 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.02110618
ELECTRON MICROSCOPYf_angle_d1.67914502
ELECTRON MICROSCOPYf_dihedral_angle_d12.41633
ELECTRON MICROSCOPYf_chiral_restr0.1041762
ELECTRON MICROSCOPYf_plane_restr0.0071671

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