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- PDB-9dqj: CryoEM structure of Gq-coupled MRGPRD with a new agonist EP-3945 -

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Entry
Database: PDB / ID: 9dqj
TitleCryoEM structure of Gq-coupled MRGPRD with a new agonist EP-3945
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Mas-related G-protein coupled receptor member D
  • scFv16
KeywordsSIGNALING PROTEIN / GPCR
Function / homology
Function and homology information


angiotensin-mediated vasodilation involved in regulation of systemic arterial blood pressure / adenylate cyclase-activating serotonin receptor signaling pathway / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / sensory perception of chemical stimulus / negative regulation of calcium ion-dependent exocytosis / G protein-coupled adenosine receptor signaling pathway / mu-type opioid receptor binding / negative regulation of adenylate cyclase activity / corticotropin-releasing hormone receptor 1 binding / positive regulation of urine volume ...angiotensin-mediated vasodilation involved in regulation of systemic arterial blood pressure / adenylate cyclase-activating serotonin receptor signaling pathway / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / sensory perception of chemical stimulus / negative regulation of calcium ion-dependent exocytosis / G protein-coupled adenosine receptor signaling pathway / mu-type opioid receptor binding / negative regulation of adenylate cyclase activity / corticotropin-releasing hormone receptor 1 binding / positive regulation of urine volume / positive regulation of neural precursor cell proliferation / negative regulation of synaptic transmission / G protein-coupled peptide receptor activity / beta-2 adrenergic receptor binding / gamma-aminobutyric acid signaling pathway / neuronal dense core vesicle / regulation of calcium ion transport / negative regulation of apoptotic signaling pathway / PKA activation in glucagon signalling / developmental growth / D1 dopamine receptor binding / Hedgehog 'off' state / Adenylate cyclase inhibitory pathway / positive regulation of vascular associated smooth muscle cell proliferation / response to prostaglandin E / adenylate cyclase regulator activity / insulin-like growth factor receptor binding / ionotropic glutamate receptor binding / response to nutrient / adenylate cyclase activator activity / hippocampal mossy fiber to CA3 synapse / positive regulation of superoxide anion generation / Regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / bone development / G-protein beta/gamma-subunit complex binding / platelet aggregation / 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 / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / 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 / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / positive regulation of cold-induced thermogenesis / retina development in camera-type eye / G protein activity / cell body / GTPase binding / Ca2+ pathway / midbody / fibroblast proliferation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / G alpha (q) signalling events / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / positive regulation of ERK1 and ERK2 cascade / ciliary basal body / positive regulation of cell migration / G protein-coupled receptor signaling pathway / apical plasma membrane
Similarity search - Function
Mas-related G protein-coupled receptor D / Mas-related G protein-coupled receptor family / G-protein alpha subunit, group S / 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 ...Mas-related G protein-coupled receptor D / Mas-related G protein-coupled receptor family / G-protein alpha subunit, group S / 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 / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / 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 / 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(s) subunit alpha isoforms XLas / Mas-related G-protein coupled receptor member D
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsCao, C. / Wang, C. / Liu, Y. / Fay, J.F. / Roth, B.L.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)R01DA055656 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)U24DK116195 United States
CitationJournal: Cell Rep / Year: 2024
Title: High-affinity agonists reveal recognition motifs for the MRGPRD GPCR.
Authors: Chunyu Wang / Yongfeng Liu / Marion Lanier / Adam Yeager / Isha Singh / Ryan H Gumpper / Brian E Krumm / Chelsea DeLeon / Shicheng Zhang / Marcus Boehm / Richard Pittner / Alain Baron / Lisa ...Authors: Chunyu Wang / Yongfeng Liu / Marion Lanier / Adam Yeager / Isha Singh / Ryan H Gumpper / Brian E Krumm / Chelsea DeLeon / Shicheng Zhang / Marcus Boehm / Richard Pittner / Alain Baron / Lisa Dvorak / Corinne Bacon / Brian K Shoichet / Esther Martinborough / Jonathan F Fay / Can Cao / Bryan L Roth /
Abstract: The human MRGPRD protein is a member of the Mas-related G protein-coupled receptors (MRGPRs) that is involved in the sensing of pain, itch, and other inflammatory stimuli. As with other MRGPRs, ...The human MRGPRD protein is a member of the Mas-related G protein-coupled receptors (MRGPRs) that is involved in the sensing of pain, itch, and other inflammatory stimuli. As with other MRGPRs, MRGPRD is a relatively understudied receptor with few known agonists. The most potent small-molecule agonist of MRGPRD reported so far is β-alanine, with an affinity in the micromole range, which largely restricts its functional study. Here, we report two MRGPRD agonists, EP-2825 and EP-3945, that are approximately 100-fold more potent than β-alanine and determine the structures of MRGPRD-Gq in complex with EP-2825 and EP-3945, respectively. The structures reveal distinct agonist binding modes of MRGPRD and large conformational plasticity of the orthosteric pocket. Collectively, the discovery of high-affinity MRGPRD agonists and their distinct binding modes will facilitate the functional study and the structure-based design of ligands targeting this understudied receptor.
History
DepositionSep 24, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 11, 2024Provider: repository / Type: Initial release
Revision 1.0Dec 11, 2024Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Dec 11, 2024Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Dec 11, 2024Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Dec 11, 2024Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Dec 11, 2024Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Dec 11, 2024Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1May 28, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1May 28, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Mas-related G-protein coupled receptor member D
B: Guanine nucleotide-binding protein G(i) subunit alpha-2,Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas
C: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
D: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
E: scFv16
hetero molecules


Theoretical massNumber of molelcules
Total (without water)137,6746
Polymers137,2555
Non-polymers4181
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 BCD

#2: Protein Guanine nucleotide-binding protein G(i) subunit alpha-2,Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas / Adenylate cyclase-inhibiting G alpha protein / Adenylate cyclase-stimulating G alpha protein / ...Adenylate cyclase-inhibiting G alpha protein / Adenylate cyclase-stimulating G alpha protein / Extra large alphas protein / XLalphas


Mass: 28084.832 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI2, GNAI2B, GNAS, GNAS1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P04899, UniProt: Q5JWF2, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37728.152 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
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Protein / Antibody / Non-polymers , 3 types, 3 molecules AE

#1: Protein Mas-related G-protein coupled receptor member D / Beta-alanine receptor / G-protein coupled receptor TGR7


Mass: 36171.523 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MRGPRD, MRGD / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8TDS7
#5: Antibody scFv16


Mass: 27409.588 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)
#6: Chemical ChemComp-A1BEQ / 2-({1-[1-(4-methoxyphenyl)cyclopropane-1-carbonyl]piperidin-4-yl}amino)quinazolin-4(3H)-one


Mass: 418.488 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H26N4O3 / 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

Component
IDNameTypeEntity IDParent-IDSource
1EP-3945-bound MRGPRD-Gq complexCOMPLEX#1-#50RECOMBINANT
2Mas-related G-protein coupled receptor member DCOMPLEX#11RECOMBINANT
3G(i) subunit alpha-2/G(s) subunit alpha isoforms XLasCOMPLEX#21RECOMBINANT
4G(I)/G(S)/G(T) subunit beta-1COMPLEX#31RECOMBINANT
5G(I)/G(S)/G(O) subunit gamma-2COMPLEX#41RECOMBINANT
6scFv16COMPLEX#51RECOMBINANT
Molecular weightValue: 0.137 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
34Homo sapiens (human)9606
45Homo sapiens (human)9606
56Mus musculus (house mouse)10090
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Spodoptera frugiperda (fall armyworm)7108
33Spodoptera frugiperda (fall armyworm)7108
44Spodoptera frugiperda (fall armyworm)7108
55Spodoptera frugiperda (fall armyworm)7108
66Spodoptera frugiperda (fall armyworm)7108
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 3000 nm / Nominal defocus min: 200 nm
Image recordingElectron dose: 56.9 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameCategory
2SerialEMimage acquisition
8PHENIXmodel refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 318286 / Symmetry type: POINT

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