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- PDB-9u4y: cryo-EM structure of Xenopus laevis GnRHR bound with mammal GnRH -

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Basic information

Entry
Database: PDB / ID: 9u4y
Titlecryo-EM structure of Xenopus laevis 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 / GnRHR / Gonadotropin-Releasing Hormone Receptor
Function / homology
Function and homology information


regulation of luteinizing hormone secretion / regulation of follicle-stimulating hormone secretion / gonadotropin hormone-releasing hormone activity / gonadotropin-releasing hormone receptor binding / protein-hormone receptor activity / positive regulation of mini excitatory postsynaptic potential / beta2-adrenergic receptor activity / negative regulation of smooth muscle contraction / AMPA selective glutamate receptor signaling pathway / positive regulation of autophagosome maturation ...regulation of luteinizing hormone secretion / regulation of follicle-stimulating hormone secretion / gonadotropin hormone-releasing hormone activity / gonadotropin-releasing hormone receptor binding / protein-hormone receptor activity / positive regulation of mini excitatory postsynaptic potential / beta2-adrenergic receptor activity / negative regulation of smooth muscle contraction / AMPA selective glutamate receptor signaling pathway / positive regulation of autophagosome maturation / norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure / heat generation / norepinephrine binding / Adrenoceptors / positive regulation of lipophagy / negative regulation of multicellular organism growth / negative regulation of G protein-coupled receptor signaling pathway / endosome to lysosome transport / response to psychosocial stress / adrenergic receptor signaling pathway / diet induced thermogenesis / positive regulation of cAMP/PKA signal transduction / adenylate cyclase binding / smooth muscle contraction / bone resorption / potassium channel regulator activity / positive regulation of bone mineralization / neuronal dense core vesicle / brown fat cell differentiation / cellular response to hormone stimulus / intercellular bridge / adenylate cyclase-activating adrenergic receptor signaling pathway / regulation of sodium ion transport / peptide binding / receptor-mediated endocytosis / response to cold / clathrin-coated endocytic vesicle membrane / G protein-coupled receptor activity / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / cellular response to amyloid-beta / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / 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 / photoreceptor disc membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / mitotic spindle / 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 / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / 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 / Cargo recognition for clathrin-mediated endocytosis / 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 / Clathrin-mediated endocytosis / positive regulation of cold-induced thermogenesis / amyloid-beta binding / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / microtubule cytoskeleton / 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 / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Ras protein signal transduction / transcription by RNA polymerase II / early endosome / cell surface receptor signaling pathway / Extra-nuclear estrogen signaling / lysosome / cell population proliferation
Similarity search - Function
Gonadotrophin-releasing hormone receptor family / Gonadoliberin I precursor / Gonadotropin-releasing hormone / Gonadoliberin / Gonadotropin-releasing hormone / Gonadotropin-releasing hormones signature. / Beta 2 adrenoceptor / Adrenoceptor family / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein, gamma subunit ...Gonadotrophin-releasing hormone receptor family / Gonadoliberin I precursor / Gonadotropin-releasing hormone / Gonadoliberin / Gonadotropin-releasing hormone / Gonadotropin-releasing hormones signature. / Beta 2 adrenoceptor / Adrenoceptor family / Serpentine type 7TM GPCR chemoreceptor Srsx / 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
Beta-2 adrenergic 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 / Progonadoliberin-1 / Gonadotropin-releasing hormone receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Ateles (mammal)
Xenopus laevis (African clawed frog)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.67 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
Revision 1.0Jun 11, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 11, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
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
C: Gonadoliberin-1
A: Guanine nucleotide-binding protein G(q) subunit alpha-1
S: scFv16
R: Beta-2 adrenergic receptor,Gonadotropin-releasing hormone receptor


Theoretical massNumber of molelcules
Total (without water)162,1686
Polymers162,1686
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 BGA

#1: 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
#2: 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
#4: 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)

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Protein/peptide / Antibody / Protein , 3 types, 3 molecules CSR

#3: Protein/peptide Gonadoliberin-1


Mass: 1183.300 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) / References: UniProt: Q28588
#5: 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)
#6: Protein Beta-2 adrenergic receptor,Gonadotropin-releasing hormone receptor / Beta-2 adrenoreceptor / Beta-2 adrenoceptor


Mass: 56891.434 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Ateles (mammal), (gene. exp.) Xenopus laevis (African clawed frog)
Gene: ADRB2, ADRB2R, B2AR, gnrhr.L, gnrhr, GNRHR1, gnrhr2-A, xgnrhr
Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P07550, UniProt: Q90WJ2

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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 Xenopus laevis GnRHR bound with mammal GnRH
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Xenopus laevis (African clawed frog)
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: 2.67 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 255764 / Symmetry type: POINT

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