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- PDB-6g79: Coupling specificity of heterotrimeric Go to the serotonin 5-HT1B... -

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Basic information

Entry
Database: PDB / ID: 6g79
TitleCoupling specificity of heterotrimeric Go to the serotonin 5-HT1B receptor
Components
  • 5-hydroxytryptamine receptor 1B
  • 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(o) subunit alpha
KeywordsMEMBRANE PROTEIN / G-protein coupled receptor / 5-HT1B / Mini-Go / serotonin
Function / homology
Function and homology information


guanyl nucleotide binding / voltage-gated calcium channel activity involved in regulation of presynaptic cytosolic calcium levels / adenylate cyclase-inhibiting serotonin receptor signaling pathway / negative regulation of gamma-aminobutyric acid secretion / G protein-coupled serotonin receptor complex / serotonergic synapse / regulation of behavior / Serotonin receptors / negative regulation of synaptic transmission, GABAergic / response to mineralocorticoid ...guanyl nucleotide binding / voltage-gated calcium channel activity involved in regulation of presynaptic cytosolic calcium levels / adenylate cyclase-inhibiting serotonin receptor signaling pathway / negative regulation of gamma-aminobutyric acid secretion / G protein-coupled serotonin receptor complex / serotonergic synapse / regulation of behavior / Serotonin receptors / negative regulation of synaptic transmission, GABAergic / response to mineralocorticoid / negative regulation of serotonin secretion / drinking behavior / cellular response to temperature stimulus / mu-type opioid receptor binding / serotonin binding / corticotropin-releasing hormone receptor 1 binding / bone remodeling / negative regulation of synaptic transmission, glutamatergic / G protein-coupled serotonin receptor activity / vasoconstriction / protein kinase C-activating G protein-coupled receptor signaling pathway / neurotransmitter receptor activity / G protein-coupled receptor internalization / dopamine receptor signaling pathway / regulation of synaptic vesicle exocytosis / regulation of dopamine secretion / heterocyclic compound binding / cellular response to alkaloid / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / calyx of Held / G protein-coupled serotonin receptor binding / positive regulation of vascular associated smooth muscle cell proliferation / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / presynaptic modulation of chemical synaptic transmission / response to cocaine / muscle contraction / 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 / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / 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 / 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 / cellular response to xenobiotic stimulus / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / GTPase binding / presynaptic membrane / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / fibroblast proliferation / chemical synaptic transmission / G alpha (s) signalling events / G alpha (q) signalling events / response to ethanol / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / dendrite / synapse / protein-containing complex binding / GTP binding / endoplasmic reticulum / signal transduction
Similarity search - Function
5-Hydroxytryptamine 1B receptor / 5-hydroxytryptamine receptor family / Transducin (heterotrimeric G protein), gamma chain / G Protein Gi Gamma 2 / Rhopdopsin 7-helix transmembrane proteins / Rhodopsin 7-helix transmembrane proteins / YVTN repeat-like/Quinoprotein amine dehydrogenase / G-protein alpha subunit, group I / 7 Propeller / Methylamine Dehydrogenase; Chain H ...5-Hydroxytryptamine 1B receptor / 5-hydroxytryptamine receptor family / Transducin (heterotrimeric G protein), gamma chain / G Protein Gi Gamma 2 / Rhopdopsin 7-helix transmembrane proteins / Rhodopsin 7-helix transmembrane proteins / YVTN repeat-like/Quinoprotein amine dehydrogenase / G-protein alpha subunit, group I / 7 Propeller / Methylamine Dehydrogenase; Chain H / Serpentine type 7TM GPCR chemoreceptor Srsx / 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 receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / Few Secondary Structures / Irregular / G-protein beta WD-40 repeat / WD40 repeat, conserved site / P-loop containing nucleotide triphosphate hydrolases / 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 / Up-down Bundle / P-loop containing nucleoside triphosphate hydrolase / Rossmann fold / 3-Layer(aba) Sandwich / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-EP5 / Guanine nucleotide-binding protein G(O) subunit alpha-like / Guanine nucleotide-binding protein G(o) subunit alpha / 5-hydroxytryptamine receptor 1B / 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
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.78 Å
AuthorsGarcia-Nafria, J. / Nehme, R. / Edwards, P. / Tate, C.G.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
European Research CouncilEMPSI 339995 United Kingdom
Medical Research Council (United Kingdom)MRC U105197215 United Kingdom
CitationJournal: Nature / Year: 2018
Title: Cryo-EM structure of the serotonin 5-HT receptor coupled to heterotrimeric G.
Authors: Javier García-Nafría / Rony Nehmé / Patricia C Edwards / Christopher G Tate /
Abstract: G-protein-coupled receptors (GPCRs) form the largest family of receptors encoded by the human genome (around 800 genes). They transduce signals by coupling to a small number of heterotrimeric G ...G-protein-coupled receptors (GPCRs) form the largest family of receptors encoded by the human genome (around 800 genes). They transduce signals by coupling to a small number of heterotrimeric G proteins (16 genes encoding different α-subunits). Each human cell contains several GPCRs and G proteins. The structural determinants of coupling of G to four different GPCRs have been elucidated, but the molecular details of how the other G-protein classes couple to GPCRs are unknown. Here we present the cryo-electron microscopy structure of the serotonin 5-HT receptor (5-HTR) bound to the agonist donitriptan and coupled to an engineered G heterotrimer. In this complex, 5-HTR is in an active state; the intracellular domain of the receptor is in a similar conformation to that observed for the β-adrenoceptor (βAR) or the adenosine A receptor (AR) in complex with G. In contrast to the complexes with G, the gap between the receptor and the Gβ-subunit in the G-5-HTR complex precludes molecular contacts, and the interface between the Gα-subunit of G and the receptor is considerably smaller. These differences are likely to be caused by the differences in the interactions with the C terminus of the G α-subunit. The molecular variations between the interfaces of G and G in complex with GPCRs may contribute substantially to both the specificity of coupling and the kinetics of signalling.
History
DepositionApr 5, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 20, 2018Provider: repository / Type: Initial release
Revision 1.1Jul 4, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_id_ISSN / _citation.journal_volume ..._citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 2.0Sep 19, 2018Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Structure summary
Category: atom_site / pdbx_poly_seq_scheme ...atom_site / pdbx_poly_seq_scheme / pdbx_struct_sheet_hbond / pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues / pdbx_validate_torsion / struct_conf / struct_ref_seq / struct_ref_seq_dif / struct_sheet_range
Item: _atom_site.auth_seq_id / _pdbx_poly_seq_scheme.pdb_seq_num ..._atom_site.auth_seq_id / _pdbx_poly_seq_scheme.pdb_seq_num / _pdbx_struct_sheet_hbond.range_1_auth_seq_id / _pdbx_struct_sheet_hbond.range_2_auth_seq_id / _pdbx_unobs_or_zero_occ_atoms.auth_seq_id / _pdbx_unobs_or_zero_occ_residues.auth_seq_id / _pdbx_validate_torsion.auth_seq_id / _struct_conf.beg_auth_seq_id / _struct_conf.end_auth_seq_id / _struct_ref_seq.pdbx_auth_seq_align_end / _struct_ref_seq_dif.pdbx_auth_seq_num / _struct_sheet_range.beg_auth_seq_id / _struct_sheet_range.end_auth_seq_id
Revision 2.1Dec 11, 2019Group: Other / Category: atom_sites
Item: _atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][1] ..._atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][1] / _atom_sites.fract_transf_matrix[2][2] / _atom_sites.fract_transf_matrix[3][2] / _atom_sites.fract_transf_matrix[3][3]

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Structure visualization

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Assembly

Deposited unit
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
A: Guanine nucleotide-binding protein G(o) subunit alpha
S: 5-hydroxytryptamine receptor 1B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)111,9645
Polymers111,5604
Non-polymers4041
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7030 Å2
ΔGint-60 kcal/mol
Surface area36120 Å2
MethodPISA

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Components

#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: Trichoplusia ni (cabbage looper) / References: UniProt: P62873
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7845.078 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P59768
#3: Protein Guanine nucleotide-binding protein G(o) subunit alpha


Mass: 25155.727 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAO1 / Production host: Escherichia coli (E. coli) / References: UniProt: P09471, UniProt: A0A0P7W0C8
#4: Protein 5-hydroxytryptamine receptor 1B / 5-HT1B / S12 / Serotonin 1D beta receptor / 5-HT-1D-beta / Serotonin receptor 1B


Mass: 41273.375 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HTR1B, HTR1DB / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P28222
#5: Chemical ChemComp-EP5 / 2-[5-[2-[4-(4-cyanophenyl)piperazin-1-yl]-2-oxidanylidene-ethoxy]-1~{H}-indol-3-yl]ethylazanium / Donitriptan


Mass: 404.485 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H26N5O2 / Comment: agonist*YM

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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
1Serotonin 5-HT1B receptor bound to a mini-Go heterotrimerCOMPLEX#1-#40RECOMBINANT
25-HT1B receptorCOMPLEX#41RECOMBINANT
3Beta subunitCOMPLEX#11RECOMBINANT
4mini-GoCOMPLEX#31RECOMBINANT
5Gamma subunitCOMPLEX#21RECOMBINANT
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
110.111438 MDaNO
2141.232 kDa/nmNO
3137.302 kDa/nmNO
4125.179 kDa/nmNO
517.834 kDa/nmNO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
43Homo sapiens (human)9606
54Homo sapiens (human)9606
65Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Trichoplusia ni (cabbage looper)7111
32Trichoplusia ni (cabbage looper)7111
43Trichoplusia ni (cabbage looper)7111
54Escherichia coli (E. coli)562
65Trichoplusia ni (cabbage looper)7111
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPES1
2100 mMNaClSodium chloride1
31 mMMgCl21
40.15 %DDM1
50.001 mMDonitriptan1
SpecimenConc.: 2.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 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: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / C2 aperture diameter: 50 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 60 sec. / Electron dose: 30 e/Å2 / Detector mode: COUNTING / Film or detector model: FEI FALCON III (4k x 4k) / Num. of real images: 5737

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Processing

EM software
IDNameVersionCategory
1RELION2.1particle selection
2EPUimage acquisition
4Gctf1.06CTF correction
7Cootmodel fitting
9RELION2.1initial Euler assignment
10RELION2.1final Euler assignment
11RELION2.1classification
12RELION2.13D reconstruction
13REFMACmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.78 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 730118 / Symmetry type: POINT

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