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- PDB-9k07: Cryo-EM structure of the DSO-5a-bound human BRS3-Gq complex -

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Entry
Database: PDB / ID: 9k07
TitleCryo-EM structure of the DSO-5a-bound human BRS3-Gq complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Bombesin receptor subtype-3,Oplophorus-luciferin 2-monooxygenase catalytic subunit
  • Nanobody-35
  • scFv16
KeywordsMEMBRANE PROTEIN / DSO-5a
Function / homology
Function and homology information


bombesin receptor activity / Oplophorus-luciferin 2-monooxygenase / Oplophorus-luciferin 2-monooxygenase activity / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / adult feeding behavior / neuropeptide receptor activity / negative regulation of calcium ion-dependent exocytosis / G protein-coupled adenosine receptor signaling pathway / negative regulation of adenylate cyclase activity / positive regulation of urine volume ...bombesin receptor activity / Oplophorus-luciferin 2-monooxygenase / Oplophorus-luciferin 2-monooxygenase activity / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / adult feeding behavior / neuropeptide receptor activity / negative regulation of calcium ion-dependent exocytosis / G protein-coupled adenosine receptor signaling pathway / negative regulation of adenylate cyclase activity / positive regulation of urine volume / positive regulation of neural precursor cell proliferation / 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 / negative regulation of synaptic transmission / Vasopressin regulates renal water homeostasis via Aquaporins / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / G alpha (i) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / 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 / 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 / photoreceptor outer segment membrane / G alpha (s) signalling events / G alpha (q) signalling events / spectrin binding / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / gamma-aminobutyric acid signaling pathway / 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 / regulation of calcium ion transport / negative regulation of apoptotic signaling pathway / PKA activation in glucagon signalling / developmental growth / hair follicle placode formation / photoreceptor outer segment / D1 dopamine receptor binding / intracellular transport / neuronal dense core vesicle / vascular endothelial cell response to laminar fluid shear stress / renal water homeostasis / activation of adenylate cyclase activity / Hedgehog 'off' state / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of superoxide anion generation / adenylate cyclase-activating adrenergic receptor signaling pathway / Adenylate cyclase inhibitory pathway / cardiac muscle cell apoptotic process / photoreceptor inner segment / response to nutrient / cellular response to glucagon stimulus / regulation of insulin secretion / bioluminescence / Peptide ligand-binding receptors / hippocampal mossy fiber to CA3 synapse / adenylate cyclase activator activity / trans-Golgi network membrane / Regulation of insulin secretion / negative regulation of inflammatory response to antigenic stimulus / G protein-coupled receptor binding / bone development / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / platelet aggregation / regulation of blood pressure / cognition / G-protein beta/gamma-subunit complex binding / adenylate cyclase-activating G protein-coupled receptor signaling pathway / glucose metabolic process
Similarity search - Function
Bombesin receptor type 3 / Bombesin receptor-like / G-protein alpha subunit, group S / G-protein alpha subunit, group I / Calycin / Serpentine type 7TM GPCR chemoreceptor Srsx / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. ...Bombesin receptor type 3 / Bombesin receptor-like / G-protein alpha subunit, group S / G-protein alpha subunit, group I / Calycin / Serpentine type 7TM GPCR chemoreceptor Srsx / 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 / G protein beta WD-40 repeat protein / 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. / 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
: / Guanine nucleotide-binding protein G(i) subunit alpha-2 / Bombesin receptor subtype-3 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Oplophorus-luciferin 2-monooxygenase catalytic subunit
Similarity search - Component
Biological speciesHomo sapiens (human)
Oplophorus gracilirostris (crustacean)
Mus musculus (house mouse)
Rattus norvegicus (Norway rat)
Bos taurus (domestic cattle)
Lama glama (llama)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.83 Å
AuthorsLi, J. / Li, C. / Zhou, Q. / Han, W. / Fang, M. / Xu, Y. / Mai, Y. / Cui, J. / Xu, H. / Zhang, Y. ...Li, J. / Li, C. / Zhou, Q. / Han, W. / Fang, M. / Xu, Y. / Mai, Y. / Cui, J. / Xu, H. / Zhang, Y. / Yin, W. / Wang, M.
Funding support China, 17items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82273961 China
National Natural Science Foundation of China (NSFC)82073904 China
National Natural Science Foundation of China (NSFC)81872915 China
National Natural Science Foundation of China (NSFC)32171189 China
National Natural Science Foundation of China (NSFC)32130022 China
National Natural Science Foundation of China (NSFC)82121005 China
Other government2022YFA1302900 China
Other government2022YFC2703105 China
Other government2021278 China
Other governmentCXTD2023010 China
Other government2019B090904008 China
Other government2021B0909050003 China
Other governmentXDB37030103 China
Other government2019SHZDZX02 China
Other governmentLG-GG-202204-01 China
Other government2021ZD0203400 China
Other governmentZDKJ2021028 China
CitationJournal: Acta Pharm Sin B / Year: 2025
Title: Divergent activation patterns of BRS3 revealed by two Chinese herb-derived agonists.
Authors: Jie Li / Changyao Li / Qingtong Zhou / Wei Han / Mingzhu Fang / Youwei Xu / Yiting Mai / Yao Zhang / Jiahua Cui / H Eric Xu / Yan Zhang / Wanchao Yin / Ming-Wei Wang /
Abstract: Bombesin receptor subtype-3 (BRS3) is an orphan G protein-coupled receptor (GPCR) that plays critical roles in energy homeostasis, glucose metabolism, and insulin secretion. Recent structural studies ...Bombesin receptor subtype-3 (BRS3) is an orphan G protein-coupled receptor (GPCR) that plays critical roles in energy homeostasis, glucose metabolism, and insulin secretion. Recent structural studies have elucidated BRS3 signaling mechanisms using synthetic ligands, including BA1 and MK-5046. However, the molecular basis of BRS3 activation by bioactive natural compounds and their derivatives, particularly those derived from traditional Chinese medicine, remains unclear. Here, we present high-resolution cryogenic electron microscopy (cryo-EM) structures of the human BRS3-G complex in both unliganded and active states bound by two herb-derived compounds (DSO-5a and oridonin), at resolutions of 2.9, 2.8, and 2.9 Å, respectively. These structures display distinct ligand recognition patterns between DSO-5a and oridonin. Although both compounds bind to the orthosteric pocket, they differentially engage the interaction network of BRS3, as demonstrated by mutagenesis studies assessing calcium mobilization and inositol phosphate 1 (IP1) accumulation. These findings enhance our understanding of BRS3 activation and provide valuable insights into the development of small-molecule BRS3 modulators with therapeutic potential.
History
DepositionOct 15, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Aug 27, 2025Provider: repository / Type: Initial release
Revision 1.1Nov 5, 2025Group: Data collection / Database references / Category: citation / em_admin
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 / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
R: Bombesin receptor subtype-3,Oplophorus-luciferin 2-monooxygenase catalytic subunit
A: Guanine nucleotide-binding protein G(i) subunit alpha-2,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
E: scFv16
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
N: Nanobody-35
hetero molecules


Theoretical massNumber of molelcules
Total (without water)185,6407
Polymers185,2006
Non-polymers4401
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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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG

#2: Protein Guanine nucleotide-binding protein G(i) subunit alpha-2,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Adenylate cyclase-inhibiting G alpha protein / Adenylate cyclase-stimulating G alpha protein


Mass: 28084.832 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Gi2-mini-Gq chimeric,Gi2-mini-Gq chimeric / Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI2, GNAI2B, GNAS, GNAS1, GSP / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P04899, UniProt: P63092, 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: 37915.496 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
#5: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7729.947 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

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Antibody , 2 types, 2 molecules EN

#3: Antibody scFv16


Mass: 28668.922 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Trichoplusia ni (cabbage looper)
#6: Antibody Nanobody-35


Mass: 15343.019 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)

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Protein / Non-polymers , 2 types, 2 molecules R

#1: Protein Bombesin receptor subtype-3,Oplophorus-luciferin 2-monooxygenase catalytic subunit / BRS-3 / 19kOLase


Mass: 67457.555 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Oplophorus gracilirostris (crustacean)
Gene: BRS3 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P32247, UniProt: Q9GV45, Oplophorus-luciferin 2-monooxygenase
#7: Chemical ChemComp-A1EL6 / [(1~{S})-1-[1,4-dimethoxy-8-nitroso-5-(oxidanylamino)naphthalen-2-yl]-2,2-dimethyl-but-3-enyl] furan-2-carboxylate


Mass: 440.446 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H24N2O7 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
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: Cryo-EM structure of the DSO-5a-bound human BRS3-miniGq complex
Type: COMPLEX / Entity ID: #1-#6 / Source: RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
31Mus musculus (house mouse)10090
41Rattus norvegicus (Norway rat)10116
51Bos taurus (domestic cattle)9913
61Lama glama (llama)9844
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Trichoplusia ni (cabbage looper)7111
31Spodoptera frugiperda (fall armyworm)7108
41Escherichia coli (E. coli)562
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

MicroscopyModel: FEI TECNAI 10
Electron gunElectron source: OTHER / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 80 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameCategory
1SerialEMparticle selection
8PHENIXmodel refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.83 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 311433 / Symmetry type: POINT
RefinementHighest resolution: 2.83 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0049831
ELECTRON MICROSCOPYf_angle_d0.49713334
ELECTRON MICROSCOPYf_dihedral_angle_d4.1911348
ELECTRON MICROSCOPYf_chiral_restr0.0421519
ELECTRON MICROSCOPYf_plane_restr0.0041684

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