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- PDB-9vaw: Cryo-EM structure of human Neurotensin Receptor 1 (hNTSR1)-Gq (de... -

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Entry
Database: PDB / ID: 9vaw
TitleCryo-EM structure of human Neurotensin Receptor 1 (hNTSR1)-Gq (delipidated) complex in nucleotide-free C state
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • JMV449
  • Neurotensin receptor type 1
  • scFv16
KeywordsMEMBRANE PROTEIN / GPCR / NTSR1 / neurotensin / G-protein
Function / homology
Function and homology information


Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / G protein-coupled neurotensin receptor activity / sensory perception of itch / inositol phosphate catabolic process / symmetric synapse / positive regulation of locomotion / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway / regulation of inositol trisphosphate biosynthetic process / PLC beta mediated events ...Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / G protein-coupled neurotensin receptor activity / sensory perception of itch / inositol phosphate catabolic process / symmetric synapse / positive regulation of locomotion / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway / regulation of inositol trisphosphate biosynthetic process / PLC beta mediated events / phospholipase C-activating serotonin receptor signaling pathway / regulation of platelet activation / entrainment of circadian clock / positive regulation of gamma-aminobutyric acid secretion / D-aspartate import across plasma membrane / positive regulation of arachidonate secretion / L-glutamate import across plasma membrane / vocalization behavior / regulation of behavioral fear response / cAMP biosynthetic process / regulation of respiratory gaseous exchange / positive regulation of inhibitory postsynaptic potential / negative regulation of systemic arterial blood pressure / regulation of canonical Wnt signaling pathway / negative regulation of release of sequestered calcium ion into cytosol / glutamate receptor signaling pathway / mast cell degranulation / positive regulation of glutamate secretion / response to food / regulation of membrane depolarization / response to lipid / temperature homeostasis / positive regulation of inositol phosphate biosynthetic process / detection of temperature stimulus involved in sensory perception of pain / response to stress / phototransduction, visible light / photoreceptor outer segment / postsynaptic cytosol / conditioned place preference / cellular response to acidic pH / hormone-mediated signaling pathway / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / Peptide ligand-binding receptors / positive regulation of release of sequestered calcium ion into cytosol / GTPase activator activity / dendritic shaft / adult locomotory behavior / neuropeptide signaling pathway / response to prostaglandin E / G protein-coupled receptor binding / G protein-coupled receptor activity / cytoplasmic side of plasma membrane / G-protein beta/gamma-subunit complex binding / blood coagulation / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G protein-coupled acetylcholine receptor signaling pathway / terminal bouton / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Glucagon signaling in metabolic regulation / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / G beta:gamma signalling through BTK / photoreceptor disc membrane / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / 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 / cellular response to prostaglandin E stimulus / heterotrimeric G-protein complex / G alpha (12/13) signalling events / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / extracellular vesicle / sensory perception of taste / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / adenylate cyclase-activating G protein-coupled receptor signaling pathway / retina development in camera-type eye / GTPase binding / fibroblast proliferation / G protein activity / Ca2+ pathway / nuclear membrane
Similarity search - Function
G-protein alpha subunit, group Q / Neurotensin receptor / Neurotensin type 1 receptor / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / G-protein, gamma subunit / G-protein gamma subunit domain profile. ...G-protein alpha subunit, group Q / Neurotensin receptor / Neurotensin type 1 receptor / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / 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 / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 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. / 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 receptor type 1 / 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
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / Resolution: 2.24 Å
AuthorsMatsui, T.E. / Kobayashi, K. / Fukuda, M. / Kawakami, K. / Yamashita, K. / Kato, H.E.
Funding support Japan, 7items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)25K09525 Japan
Japan Society for the Promotion of Science (JSPS)24H02262 Japan
Japan Society for the Promotion of Science (JSPS)25H01338 Japan
Japan Society for the Promotion of Science (JSPS)24KJ0981 Japan
Japan Society for the Promotion of Science (JSPS)25H02243 Japan
Japan Society for the Promotion of Science (JSPS)24K18060 Japan
Japan Society for the Promotion of Science (JSPS)23KJ0363 Japan
CitationJournal: Nature / Year: 2026
Title: The dynamic basis of G-protein recognition and activation by a GPCR.
Authors: Kazuhiro Kobayashi / Kouki Kawakami / Toshiki E Matsui / Shun Yokoi / Masahiro Fukuda / Tomohiro J Narita / Hiroki Arai / Mai Tambo / Takashi Sumikama / Manae Tatsumi / Keitaro Yamashita / ...Authors: Kazuhiro Kobayashi / Kouki Kawakami / Toshiki E Matsui / Shun Yokoi / Masahiro Fukuda / Tomohiro J Narita / Hiroki Arai / Mai Tambo / Takashi Sumikama / Manae Tatsumi / Keitaro Yamashita / Junki Koyanagi / Mai Kugawa / Hisako Ikeda / Ayumi Sumino / Ayori Mitsutake / Brian K Kobilka / Asuka Inoue / Hideaki E Kato /
Abstract: G-protein-coupled receptor (GPCR) signalling occurs through heterotrimeric G proteins, whose selective activation leads to distinct cellular outcomes. Although more than 200 GPCR-G protein complex ...G-protein-coupled receptor (GPCR) signalling occurs through heterotrimeric G proteins, whose selective activation leads to distinct cellular outcomes. Although more than 200 GPCR-G protein complex structures have been determined, these static snapshots provide limited insight into the dynamics of G-protein association and dissociation. Here we present cryo-electron microscopy structures of human neurotensin receptor type 1 (NTSR1) with minimally modified G and G, showing how the receptor's intracellular surface dynamically rearranges to accommodate each G-protein subtype. Furthermore, time-resolved cryo-electron microscopy analyses of NTSR1-G visualized G-protein dissociation processes on GDP/GTP binding. Characterization of more than 20 intermediates, complemented by mutational and computational analyses, identifies four key mechanistic features. First, GDP/GTP induces G release from both canonical and non-canonical active conformations with distinct kinetics. Second, NTSR1 uses common intracellular rearrangements to recognize different G-protein subtypes and to promote activation of a single subtype. Third, separation from Gβγ involves stepwise remodelling of the Gα switches I-III. Finally, G dissociates from the receptor through a pathway that is distinct from that of G, and the canonical and non-canonical NTSR1-G complexes further diverge in their dissociation trajectories. These findings provide a comprehensive framework for understanding GPCR signalling dynamics and guiding signal-targeted therapeutic development.
History
DepositionJun 4, 2025Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 3, 2026Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
R: Neurotensin receptor type 1
L: JMV449
A: Guanine nucleotide-binding protein G(q) subunit alpha
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
C: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
D: scFv16


Theoretical massNumber of molelcules
Total (without water)165,7236
Polymers165,7236
Non-polymers00
Water3,693205
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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

#3: Protein Guanine nucleotide-binding protein G(q) subunit alpha / Guanine nucleotide-binding protein alpha-q


Mass: 41365.066 Da / Num. of mol.: 1 / Mutation: C3S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAQ, GAQ / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P50148, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 39430.137 Da / Num. of mol.: 1 / Mutation: T159I
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
#5: 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 / Mutation: C68S
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

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Protein / Protein/peptide / Antibody / Non-polymers , 4 types, 208 molecules RLD

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


Mass: 48535.051 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NTSR1, NTRR / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P30989
#2: Protein/peptide JMV449


Mass: 762.979 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#6: Antibody scFv16


Mass: 27784.896 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Trichoplusia ni ascovirus 2a
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 205 / Source method: isolated from a natural source / Formula: H2O

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Details

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
1JMV449-bound human Neurotensin Receptor 1 (hNTSR1)-GqiN18 complex in nucleotide-free C state with scFv16COMPLEX#1-#60MULTIPLE SOURCES
2JMV449-bound human neurotensin receptor type 1COMPLEX#1-#21RECOMBINANT
3heterotrimeric GqiN18 protein with delipidation mutationsCOMPLEX#3-#51RECOMBINANT
4scFv16COMPLEX#61RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
22Homo sapiens (human)9606
33Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Spodoptera frugiperda (fall armyworm)7108
33Trichoplusia ni (cabbage looper)7111
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: NO
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3

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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: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1600 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 55 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 2.24 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1092577 / Symmetry type: POINT
RefinementResolution: 2.24→2.24 Å / Cor.coef. Fo:Fc: 0.876 / SU B: 2.265 / SU ML: 0.054 / ESU R: 0.101
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflection
Rwork0.34565 --
obs0.34565 477621 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 88.752 Å2
Refinement stepCycle: 1 / Total: 9335
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0050.0129329
ELECTRON MICROSCOPYr_bond_other_d00.0168717
ELECTRON MICROSCOPYr_angle_refined_deg1.0611.64112661
ELECTRON MICROSCOPYr_angle_other_deg0.3761.56620006
ELECTRON MICROSCOPYr_dihedral_angle_1_deg6.14151164
ELECTRON MICROSCOPYr_dihedral_angle_2_deg3.141263
ELECTRON MICROSCOPYr_dihedral_angle_3_deg13.098101528
ELECTRON MICROSCOPYr_dihedral_angle_4_deg
ELECTRON MICROSCOPYr_chiral_restr0.0520.21449
ELECTRON MICROSCOPYr_gen_planes_refined0.0050.0210903
ELECTRON MICROSCOPYr_gen_planes_other0.0010.022245
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it6.0718.5174676
ELECTRON MICROSCOPYr_mcbond_other6.0698.5164676
ELECTRON MICROSCOPYr_mcangle_it8.98815.2995826
ELECTRON MICROSCOPYr_mcangle_other8.98715.35827
ELECTRON MICROSCOPYr_scbond_it7.3029.2894653
ELECTRON MICROSCOPYr_scbond_other7.3019.294654
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other11.74416.7316834
ELECTRON MICROSCOPYr_long_range_B_refined17.404101.9639278
ELECTRON MICROSCOPYr_long_range_B_other17.415102.1139048
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork2.307 35233 -
obs--99.99 %

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