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- EMDB-72732: Gbg crosslinked to PLCb3 - second conformation -

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Basic information

Entry
Database: EMDB / ID: EMD-72732
TitleGbg crosslinked to PLCb3 - second conformation
Map data
Sample
  • Complex: BMOE-crosslinked complex of Gb1g2 and PLCb3
    • Protein or peptide: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
KeywordsG protein / heterotrimeric G protein / lipase / phospholipase / SIGNALING PROTEIN
Function / homology
Function and homology information


phosphoinositide phospholipase C / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / Olfactory Signaling Pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / phosphatidylinositol metabolic process / PLC beta mediated events / phospholipase C-activating serotonin receptor signaling pathway / regulation of systemic arterial blood pressure ...phosphoinositide phospholipase C / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / Olfactory Signaling Pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / phosphatidylinositol metabolic process / PLC beta mediated events / phospholipase C-activating serotonin receptor signaling pathway / regulation of systemic arterial blood pressure / phosphatidylinositol-4,5-bisphosphate phospholipase C activity / C-type glycerophospholipase activity / Activation of the phototransduction cascade / 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 / G alpha (s) signalling events / G alpha (q) signalling events / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / phosphatidylinositol-mediated signaling / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / Synthesis of IP3 and IP4 in the cytosol / postsynaptic cytosol / lipid catabolic process / release of sequestered calcium ion into cytosol / molecular function activator activity / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / photoreceptor disc membrane / cellular response to catecholamine stimulus / adenylate cyclase-activating dopamine receptor signaling pathway / G-protein beta-subunit binding / cellular response to prostaglandin E stimulus / heterotrimeric G-protein complex / sensory perception of taste / signaling receptor complex adaptor activity / retina development in camera-type eye / GTPase binding / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / molecular adaptor activity / calmodulin binding / cell population proliferation / cadherin binding / G protein-coupled receptor signaling pathway / GTPase activity / calcium ion binding / synapse / protein-containing complex binding / protein-containing complex / membrane / nucleus / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Phospholipase C-beta, C-terminal domain / PLC-beta C terminal / PLC-beta, PH domain / Phospholipase C-beta, C-terminal domain superfamily / : / PH domain / Phosphoinositide phospholipase C beta1-4-like EF-hand domain / Phosphatidylinositol-4, 5-bisphosphate phosphodiesterase beta / Phosphoinositide phospholipase C family / Phospholipase C, phosphatidylinositol-specific, Y domain ...Phospholipase C-beta, C-terminal domain / PLC-beta C terminal / PLC-beta, PH domain / Phospholipase C-beta, C-terminal domain superfamily / : / PH domain / Phosphoinositide phospholipase C beta1-4-like EF-hand domain / Phosphatidylinositol-4, 5-bisphosphate phosphodiesterase beta / Phosphoinositide phospholipase C family / Phospholipase C, phosphatidylinositol-specific, Y domain / Phosphatidylinositol-specific phospholipase C, Y domain / Phosphatidylinositol-specific phospholipase Y-box domain profile. / Phospholipase C, catalytic domain (part); domain Y / Phosphatidylinositol-specific phospholipase C, X domain / Phosphatidylinositol-specific phospholipase C, X domain / Phospholipase C, catalytic domain (part); domain X / Phosphatidylinositol-specific phospholipase X-box domain profile. / PLC-like phosphodiesterase, TIM beta/alpha-barrel domain superfamily / Protein kinase C conserved region 2 (CalB) / C2 domain / C2 domain / C2 domain profile. / C2 domain superfamily / 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 / EF-hand domain pair / 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
Similarity search - Domain/homology
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 / 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3
Similarity search - Component
Biological speciesHomo sapiens (human) / Bos taurus (domestic cattle)
Methodsingle particle reconstruction / cryo EM / Resolution: 7.0 Å
AuthorsFisher IJ / Lyon AM
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)1F32 GM145110 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)1R01 HL141076 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)1R01 GM152701 United States
CitationJournal: bioRxiv / Year: 2026
Title: Gβγ engages PLCβ3 at multiple sites to reorient and facilitate its activation.
Authors: Isaac J Fisher / Kanishka Senarath / Kennedy Outlaw / Kaushik Muralidharan / Elisabeth E Garland-Kuntz / Michelle Van Camp / Tommy Komay / Asuka Inoue / Eva Kostenis / Nevin A Lambert / Angeline M Lyon /
Abstract: Phospholipase C β (PLCβ) enzymes are activated by heterotrimeric G protein subunits, increasing hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP2) at the plasma membrane. All four human ...Phospholipase C β (PLCβ) enzymes are activated by heterotrimeric G protein subunits, increasing hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP2) at the plasma membrane. All four human PLCβ isoforms (PLCβ1-4) are activated by Gα, while PLCβ1-3 are activated to varying extents by Gβγ. The binding sites for Gα on PLCβ are well-established and much has been learned about its mechanism of activation, but comparatively little is known about Gβγ-dependent activation. In this work, we used cryo-electron microscopy (cryo-EM) single particle analysis (SPA), functional assays, and bioluminescence resonance energy transfer (BRET) to investigate how Gβγ interacts with PLCβ3 in concert with activated Gα to regulate phospholipase activity. Gβγ heterodimers bind multiple surfaces of PLCβ3 to promote activation but alone do not recruit the enzyme to the plasma membrane. Instead, Gβγ facilitates activation by Gα, most likely by reorienting the phospholipase catalytic site at the membrane to maximize PIP2 hydrolysis and downstream Ca release. Cell-based functional assays demonstrate that Gβγ is required for maximal PLCβ3 activation even when G heterotrimers are the sole source of Gβγ. Together, these findings demonstrate that Gβγ acts as a critical positive allosteric modulator that regularly acts in concert with Gα to activate PLCβ3 at the plasma membrane.
History
DepositionSep 16, 2025-
Header (metadata) releaseFeb 18, 2026-
Map releaseFeb 18, 2026-
UpdateFeb 18, 2026-
Current statusFeb 18, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_72732.png

Downloads & links

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Map

FileDownload / File: emd_72732.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.35 Å/pix.
x 256 pix.
= 344.96 Å		1.35 Å/pix.
x 256 pix.
= 344.96 Å		1.35 Å/pix.
x 256 pix.
= 344.96 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.3475 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.11
Minimum - Maximum-0.38079795 - 0.7621676
Average (Standard dev.)0.0004636257 (±0.014415493)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 344.96 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_72732_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_72732_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : BMOE-crosslinked complex of Gb1g2 and PLCb3

EntireName: BMOE-crosslinked complex of Gb1g2 and PLCb3
Components
  • Complex: BMOE-crosslinked complex of Gb1g2 and PLCb3
    • Protein or peptide: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Supramolecule #1: BMOE-crosslinked complex of Gb1g2 and PLCb3

SupramoleculeName: BMOE-crosslinked complex of Gb1g2 and PLCb3 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 156 KDa

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Macromolecule #1: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3

MacromoleculeName: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: phosphoinositide phospholipase C
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 99.653891 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MAHHHHHHGT ALQLEPPTVV ETLRRGSKFI KWDEETSSRN LVTLRVDPNG FFLYWTGPNM CVDTLDISSI RDTRTGRYAR LPKDPKIRE VLGFGGPDAR LEEKLMTVVS GPDPVNTVFL NFMAVQDDTA KVWSEELFKL AMNILAQNAS RNTFLRKAYT K LKLQVNQD ...String:
MAHHHHHHGT ALQLEPPTVV ETLRRGSKFI KWDEETSSRN LVTLRVDPNG FFLYWTGPNM CVDTLDISSI RDTRTGRYAR LPKDPKIRE VLGFGGPDAR LEEKLMTVVS GPDPVNTVFL NFMAVQDDTA KVWSEELFKL AMNILAQNAS RNTFLRKAYT K LKLQVNQD GRIPVKNILK MFSADKKRVE TALESSGLKF NRSESIRPDE FSLEIFERFL NKLSLRPDID KILLEIGAKG KP YLTLEQL MDFINQKQRD PRLNEVLYPP LRPSQARLLI EKYEPNQQFL ERDQMSMEGF SRYLGGEENG ILPLEALDLS TDM TQPLSA YFINSSHNTY LTAGQLAGTS SVEMYRQALL WGSRCVELDV WKGRPPEEEP FITHGFTMTT EVPLRDVLEA IAET AFKTS PYPVILSFEN HVDSAKQQAK MAEYCRSIFG DALLIEPLDK YPLAPGVPLP SPQDLMGRIL VKNKKRHRPS AGGPD SAGR KRPLEQSNSA LSESSAATEP SSPQLGSPSS DSCPGLSNGE EVGLEKPSLE PQKSLGDEGL NRGPYVLGPA DREDEE EDE EEEEQTDPKK PTTDEGTASS EVNATEEMST LVNYIEPVKF KSFEAARKRN KCFEMSSFVE TKAMEQLTKS PMEFVEY NK QQLSRIYPKG TRVDSSNYMP QLFWNVGCQL VALNFQTLDV AMQLNAGVFE YNGRSGYLLK PEFMRRPDKS FDPFTEVI V DGIVANALRV KVISGQFLSD RKVGIYVEVD MFGLPVDTRR KYRTRTSQGN SFNPVWDEEP FDFPKVVLPT LASLRIAAF EEGGKFVGHR ILPVSAIRSG YHYVSLRNEA NQPLSLPALL IYTEASDYIP DDHQDYAEAL INPIKHVSLM DQRARQLAAL IGE

UniProtKB: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3

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

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Bos taurus (domestic cattle)
Molecular weightTheoretical: 36.485914 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: RQEAEQLKNQ IRDARKACAD ATLSQITNNI DPVGRIQMRT RRTLRGHLAK IYAMHWGTDS RLLVSASQDG KLIIWDSYTT NKVHAIPLR SSWVMTCAYA PSGNYVACGG LDNICSIYNL KTREGNVRVS RELAGHTGYL SCCRFLDDNQ IVTSSGDTTC A LWDIETGQ ...String:
RQEAEQLKNQ IRDARKACAD ATLSQITNNI DPVGRIQMRT RRTLRGHLAK IYAMHWGTDS RLLVSASQDG KLIIWDSYTT NKVHAIPLR SSWVMTCAYA PSGNYVACGG LDNICSIYNL KTREGNVRVS RELAGHTGYL SCCRFLDDNQ IVTSSGDTTC A LWDIETGQ QTTTFTGHTG DVMSLSLAPD TRLFVSGACD ASAKLWDVRE GMCRQTFTGH ESDINAICFF PNGNAFATGS DD ATCRLFD LRADQELMTY SHDNIICGIT SVSFSKSGRL LLAGYDDFNC NVWDALKADR AGVLAGHDNR VSCLGVTDDG MAV ATGSWD SFLKIW

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Bos taurus (domestic cattle)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1 mg/mL
BufferpH: 7.4
Details: 20 mM HEPES pH 7.4, 100 mM NaCl, 0.1 mM EDTA and 0.1 mM EGTA
GridModel: Quantifoil R1.2/1.3 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 53.69 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: CTFFIND / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

4gnk


Details: PDB ID 4GNK was used as the initial model of PLCb3, and PDB ID 1GP2 as the initial model of Gbg.
Final reconstructionResolution.type: BY AUTHOR / Resolution: 7.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software: (Name: Coot, PHENIX) / Number images used: 65306
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC

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Atomic model buiding 1

Initial model
PDB IDChain

4gnk

source_name: PDB, initial_model_type: experimental model

1gp2

source_name: PDB, initial_model_type: experimental model
DetailsCrystal structures of Gbetagamma and PLCbeta3 (PDB IDs 1GP2 and 4GNK) were rigid-body fit into the cryo-EM map using Chimera. The model was refined using molecular dynamic flexible fitting (MDFF). MDFF configuration files were generated using VMD. During MDFF simulation, Gbetagamma was set as rigid with domain restraints. The MDFF simulation was conducted with a grid scaling value of 0.5 for 100 ps, followed by 3,000 steps of energy minimization until convergence of the protein RMSD. The MDFF generated model was inspected and manually adjusted in Coot, guided through the use of deep-learning-based amino-acid-wise model quality (DAQ) scoring, and refined in PHENIX.
RefinementProtocol: FLEXIBLE FIT
Output model

PDB-9yao:
Gbg crosslinked to PLCb3 - second conformation

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