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- PDB-7l0p: Structure of NTS-NTSR1-Gi complex in lipid nanodisc, canonical st... -

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Entry
Database: PDB / ID: 7l0p
TitleStructure of NTS-NTSR1-Gi complex in lipid nanodisc, canonical state, without AHD
Components
  • Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
  • Guanine nucleotide-binding protein G(T) subunit gamma-T1
  • Guanine nucleotide-binding protein G(i) subunit alpha-1
  • Neurotensin
  • Neurotensin receptor type 1
KeywordsSIGNALING PROTEIN / GPCR / NTSR1 / NTS / G protein / Nanodisc
Function / homology
Function and homology information


response to antipsychotic drug / Peptide ligand-binding receptors / neuropeptide receptor binding / G protein-coupled neurotensin receptor activity / inositol phosphate catabolic process / symmetric synapse / eye photoreceptor cell development / response to mineralocorticoid / D-aspartate import across plasma membrane / positive regulation of gamma-aminobutyric acid secretion ...response to antipsychotic drug / Peptide ligand-binding receptors / neuropeptide receptor binding / G protein-coupled neurotensin receptor activity / inositol phosphate catabolic process / symmetric synapse / eye photoreceptor cell development / response to mineralocorticoid / D-aspartate import across plasma membrane / positive regulation of gamma-aminobutyric acid secretion / positive regulation of inhibitory postsynaptic potential / regulation of membrane depolarization / positive regulation of arachidonate secretion / L-glutamate import across plasma membrane / neuron spine / regulation of respiratory gaseous exchange / neuropeptide hormone activity / digestive tract development / positive regulation of glutamate secretion / hyperosmotic response / negative regulation of systemic arterial blood pressure / negative regulation of release of sequestered calcium ion into cytosol / G alpha (q) signalling events / positive regulation of inositol phosphate biosynthetic process / response to corticosterone / temperature homeostasis / response to lipid / cellular response to lithium ion / detection of temperature stimulus involved in sensory perception of pain / phototransduction / neuropeptide signaling pathway / response to axon injury / T cell migration / D2 dopamine receptor binding / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / G protein-coupled serotonin receptor binding / cellular response to forskolin / axon terminus / regulation of mitotic spindle organization / cardiac muscle cell apoptotic process / transport vesicle / response to amphetamine / photoreceptor inner segment / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / cellular response to dexamethasone stimulus / blood vessel diameter maintenance / liver development / adult locomotory behavior / cellular response to nerve growth factor stimulus / positive regulation of release of sequestered calcium ion into cytosol / learning / dendritic shaft / response to cocaine / Regulation of insulin secretion / G protein-coupled receptor binding / visual learning / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Activation of the phototransduction cascade / terminal bouton / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / response to peptide hormone / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / cytoplasmic side of plasma membrane / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / GDP binding / cellular response to prostaglandin E stimulus / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / protein localization
Similarity search - Function
Neurotensin/neuromedin N / Neurotensin/neuromedin N precursor / Neurotensin receptor / Neurotensin type 1 receptor / 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 ...Neurotensin/neuromedin N / Neurotensin/neuromedin N precursor / Neurotensin receptor / Neurotensin type 1 receptor / 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 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) / 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
Neurotensin/neuromedin N / Neurotensin receptor type 1 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(i) subunit alpha-1 / Guanine nucleotide-binding protein G(T) subunit gamma-T1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.1 Å
AuthorsZhang, M. / Gui, M. / Wang, Z. / Gorgulla, C. / Yu, J.J. / Wu, H. / Sun, Z. / Klenk, C. / Merklinger, L. / Morstein, L. ...Zhang, M. / Gui, M. / Wang, Z. / Gorgulla, C. / Yu, J.J. / Wu, H. / Sun, Z. / Klenk, C. / Merklinger, L. / Morstein, L. / Hagn, F. / Pluckthun, A. / Brown, A. / Nasr, M.L. / Wagner, G.
CitationJournal: Nat Struct Mol Biol / Year: 2021
Title: Cryo-EM structure of an activated GPCR-G protein complex in lipid nanodiscs.
Authors: Meng Zhang / Miao Gui / Zi-Fu Wang / Christoph Gorgulla / James J Yu / Hao Wu / Zhen-Yu J Sun / Christoph Klenk / Lisa Merklinger / Lena Morstein / Franz Hagn / Andreas Plückthun / Alan ...Authors: Meng Zhang / Miao Gui / Zi-Fu Wang / Christoph Gorgulla / James J Yu / Hao Wu / Zhen-Yu J Sun / Christoph Klenk / Lisa Merklinger / Lena Morstein / Franz Hagn / Andreas Plückthun / Alan Brown / Mahmoud L Nasr / Gerhard Wagner /
Abstract: G-protein-coupled receptors (GPCRs) are the largest superfamily of transmembrane proteins and the targets of over 30% of currently marketed pharmaceuticals. Although several structures have been ...G-protein-coupled receptors (GPCRs) are the largest superfamily of transmembrane proteins and the targets of over 30% of currently marketed pharmaceuticals. Although several structures have been solved for GPCR-G protein complexes, few are in a lipid membrane environment. Here, we report cryo-EM structures of complexes of neurotensin, neurotensin receptor 1 and Gαβγ in two conformational states, resolved to resolutions of 4.1 and 4.2 Å. The structures, determined in a lipid bilayer without any stabilizing antibodies or nanobodies, reveal an extended network of protein-protein interactions at the GPCR-G protein interface as compared to structures obtained in detergent micelles. The findings show that the lipid membrane modulates the structure and dynamics of complex formation and provide a molecular explanation for the stronger interaction between GPCRs and G proteins in lipid bilayers. We propose an allosteric mechanism for GDP release, providing new insights into the activation of G proteins for downstream signaling.
History
DepositionDec 12, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 6, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 10, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Mar 24, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Nov 6, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update

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Structure visualization

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Assembly

Deposited unit
C: Neurotensin receptor type 1
D: Neurotensin
A: Guanine nucleotide-binding protein G(i) subunit alpha-1
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(T) subunit gamma-T1


Theoretical massNumber of molelcules
Total (without water)128,5625
Polymers128,5625
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area9550 Å2
ΔGint-62 kcal/mol
Surface area38120 Å2

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Components

#1: Protein Neurotensin receptor type 1 / NTR1 / High-affinity levocabastine-insensitive neurotensin receptor / NTRH


Mass: 37483.016 Da / Num. of mol.: 1
Mutation: A86L, H103D, H105Y, A161V, R213L, V234L, I253A, H305R, F358V, S362A, del273-290
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Ntsr1, Ntsr / Production host: Escherichia coli (E. coli) / References: UniProt: P20789
#2: Protein/peptide Neurotensin


Mass: 1087.277 Da / Num. of mol.: 1 / Fragment: residues 157-162
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Nts / Production host: Escherichia coli (E. coli) / References: UniProt: P20068
#3: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40415.031 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63096
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 39983.727 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
#5: Protein Guanine nucleotide-binding protein G(T) subunit gamma-T1 / Transducin gamma chain


Mass: 9593.011 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNGT1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63211
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

Component
IDNameTypeEntity IDParent-IDSource
1NTS-NTSR1-Gi complex in lipid nanodiscCOMPLEXall0RECOMBINANT
2NTSR1COMPLEX#11RECOMBINANT
3NTSCOMPLEX#21RECOMBINANT
4G(i) subunit alpha-1COMPLEX#31RECOMBINANT
5G(I)/G(S)/G(T) subunit beta-1COMPLEX#41RECOMBINANT
6G(T) subunit gamma-1COMPLEX#51RECOMBINANT
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
11NO
210.037 MDaNO
310.001 MDaNO
410.040 MDaNO
510.04 MDaNO
610.01 MDaNO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Rattus norvegicus (Norway rat)10116
23Rattus norvegicus (Norway rat)10116
34Homo sapiens (human)9606
45Homo sapiens (human)9606
56Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Escherichia coli (E. coli)562
23Escherichia coli (E. coli)562
34Spodoptera frugiperda (fall armyworm)7108
45Spodoptera frugiperda (fall armyworm)7108
56Spodoptera frugiperda (fall armyworm)7108
Buffer solutionpH: 6.9
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER
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 FIELD
Image recordingElectron dose: 57 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: dev_3318: / Classification: refinement
EM software
IDNameVersionCategory
2SerialEM3.6image acquisition
4CTFFIND4CTF correction
5RELION3.1CTF correction
8UCSF Chimera1.14model fitting
10RELION3.1initial Euler assignment
11RELIONfinal Euler assignment
13RELION3.13D reconstruction
14PHENIX1.18.2model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 4367542
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 4.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 575791 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0067099
ELECTRON MICROSCOPYf_angle_d1.059622
ELECTRON MICROSCOPYf_dihedral_angle_d5.0754192
ELECTRON MICROSCOPYf_chiral_restr0.0581114
ELECTRON MICROSCOPYf_plane_restr0.0071207

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