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- PDB-9u4w: cryo-EM structure of pig GnRHR bound with mammal GnRH -

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Basic information

Entry
Database: PDB / ID: 9u4w
Titlecryo-EM structure of pig GnRHR bound with mammal GnRH
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Beta-2 adrenergic receptor,Gonadotropin-releasing hormone receptor
  • Gonadoliberin-1
  • scFv16
KeywordsMEMBRANE PROTEIN / Cryo-EM / gonadotropin releasing hormone receptor / GnRHR
Function / homology
Function and homology information


gonadotropin-releasing hormone receptor activity / negative regulation of immature T cell proliferation / neurosecretory vesicle / regulation of ovarian follicle development / regulation of signaling / response to prolactin / Hormone ligand-binding receptors / G alpha (q) signalling events / gonadotropin hormone-releasing hormone activity / gonadotropin-releasing hormone receptor binding ...gonadotropin-releasing hormone receptor activity / negative regulation of immature T cell proliferation / neurosecretory vesicle / regulation of ovarian follicle development / regulation of signaling / response to prolactin / Hormone ligand-binding receptors / G alpha (q) signalling events / gonadotropin hormone-releasing hormone activity / gonadotropin-releasing hormone receptor binding / Hormone ligand-binding receptors / negative regulation of neuron migration / response to potassium ion / male sex determination / response to steroid hormone / cytoplasmic side of rough endoplasmic reticulum membrane / Golgi-associated vesicle / response to testosterone / estrous cycle / cellular response to hormone stimulus / response to prostaglandin E / axon terminus / female pregnancy / hormone activity / 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 / 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 / ADP signalling through P2Y purinoceptor 1 / cellular response to catecholamine stimulus / 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 / cell-cell signaling / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / regulation of gene expression / retina development in camera-type eye / GTPase binding / Ca2+ pathway / fibroblast proliferation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / response to ethanol / G alpha (i) signalling events / response to lipopolysaccharide / perikaryon / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / dendrite / synapse / negative regulation of apoptotic process / protein-containing complex binding / signal transduction / extracellular space / extracellular exosome / extracellular region / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Gonadotrophin-releasing hormone receptor family / Gonadoliberin I precursor / Gonadotropin-releasing hormone / Gonadoliberin / Gonadotropin-releasing hormone / Gonadotropin-releasing hormones signature. / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily ...Gonadotrophin-releasing hormone receptor family / Gonadoliberin I precursor / Gonadotropin-releasing hormone / Gonadoliberin / Gonadotropin-releasing hormone / Gonadotropin-releasing hormones signature. / 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
Similarity search - Domain/homology
Progonadoliberin-1 / Gonadotropin-releasing hormone receptor / 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)
Sus scrofa (pig)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.18 Å
AuthorsShen, S. / Xu, H.E.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: Cryo-EM structures of GnRHR: Foundations for next-generation therapeutics.
Authors: Shiyi Shen / Xinheng He / Heng Liu / Wen Hu / H Eric Xu / Jia Duan /
Abstract: Gonadotropin-releasing hormone receptor (GnRHR) is critical for reproductive health and a key therapeutic target for endocrine disorders and hormone-responsive cancers. Using high-resolution ...Gonadotropin-releasing hormone receptor (GnRHR) is critical for reproductive health and a key therapeutic target for endocrine disorders and hormone-responsive cancers. Using high-resolution cryoelectron microscopy, we determined the structures of and GnRHRs bound to mammal GnRH, uncovering conserved and species-specific mechanisms of receptor activation and G protein coupling. The conserved "U"-shaped GnRH conformation mediates high-affinity binding through key interactions with residues such as K, Y, and Y. Species-specific variations in extracellular loops and receptor-ligand contacts fine-tune receptor function, while ligand binding induces structural rearrangements, including N terminus displacement and TM6 rotation, critical for signaling. Structure-activity relationship analysis demonstrates how D-amino acid substitutions in GnRH analogs enhance stability and receptor affinity. Distinct binding modes of agonists and antagonists elucidate mechanisms of ligand-dependent activation and inactivation. These insights lay the groundwork for designing next-generation GnRHR therapeutics with enhanced specificity and efficacy for conditions like endometriosis, prostate cancer, and infertility.
History
DepositionMar 20, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jun 11, 2025Provider: repository / Type: Initial release
Revision 1.0Jun 11, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jun 11, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Jun 11, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 11, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jul 2, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(q) subunit alpha-1
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
F: Gonadoliberin-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
R: Beta-2 adrenergic receptor,Gonadotropin-releasing hormone receptor
S: scFv16


Theoretical massNumber of molelcules
Total (without water)152,5186
Polymers152,5186
Non-polymers00
Water00
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 ABG

#1: Protein Guanine nucleotide-binding protein G(q) subunit alpha-1


Mass: 28084.832 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37784.301 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/peptide / Protein / Antibody , 3 types, 3 molecules FRS

#3: Protein/peptide Gonadoliberin-1 / Gonadoliberin I / Gonadorelin / Gonadotropin-releasing hormone I / GnRH-I / Luliberin I / ...Gonadoliberin I / Gonadorelin / Gonadotropin-releasing hormone I / GnRH-I / Luliberin I / Luteinizing hormone-releasing hormone I / LH-RH I


Mass: 1183.300 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P01148
#5: Protein Beta-2 adrenergic receptor,Gonadotropin-releasing hormone receptor / GnRH receptor / GnRH-R / Luteinizing hormone-releasing hormone receptor / LHRH


Mass: 47241.773 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Sus scrofa (pig)
Gene: ADRB2, ADRB2R, B2AR, GNRHR / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P49922
#6: Antibody scFv16


Mass: 30363.043 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)

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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 pig GnRHR bound with mammal GnRH / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Sus scrofa (pig)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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: FLOOD BEAM
Electron lensMode: DARK FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.19.2_4158 / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.18 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 118050 / Symmetry type: POINT

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