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- PDB-9kfi: Cryo-EM structure of the human relaxin family peptide receptor 3 ... -

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Entry
Database: PDB / ID: 9kfi
TitleCryo-EM structure of the human relaxin family peptide receptor 3 in complex with relaxin-3 and G protein
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Relaxin-3 A chain
  • Relaxin-3 B chain
  • Soluble cytochrome b562,Relaxin-3 receptor 1,LgBiT
  • scFv16
KeywordsSTRUCTURAL PROTEN/IMMUNE SYSTEM / human relaxin family peptide receptor 3 / G protein-coupled receptor / ligand recognition / STRUCTURAL PROTEIN / STRUCTURAL PROTEN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


Relaxin receptors / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / 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 / negative regulation of synaptic transmission / G protein-coupled peptide receptor activity / gamma-aminobutyric acid signaling pathway ...Relaxin receptors / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / 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 / negative regulation of synaptic transmission / G protein-coupled peptide receptor activity / gamma-aminobutyric acid signaling pathway / positive regulation of cytokinesis / regulation of calcium ion transport / negative regulation of apoptotic signaling pathway / neuropeptide signaling pathway / neuronal dense core vesicle / Adenylate cyclase inhibitory pathway / positive regulation of superoxide anion generation / positive regulation of vascular associated smooth muscle cell proliferation / response to nutrient / hippocampal mossy fiber to CA3 synapse / Regulation of insulin secretion / G protein-coupled receptor activity / electron transport chain / G protein-coupled receptor binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / hormone activity / G-protein beta/gamma-subunit complex binding / 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 / 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 / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / 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 / G alpha (q) signalling events / Ras protein signal transduction / periplasmic space / electron transfer activity / 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 / iron ion binding / lysosomal membrane / cell division / GTPase activity / positive regulation of cell population proliferation / heme binding / dendrite / synapse / centrosome / GTP binding / protein-containing complex binding / signal transduction / extracellular exosome / extracellular region
Similarity search - Function
: / : / Insulin family / Insulin-like / Insulin/IGF/Relaxin family / Insulin / insulin-like growth factor / relaxin family. / Insulin, conserved site / Insulin family signature. / Insulin-like superfamily / Cytochrome b562 ...: / : / Insulin family / Insulin-like / Insulin/IGF/Relaxin family / Insulin / insulin-like growth factor / relaxin family. / Insulin, conserved site / Insulin family signature. / Insulin-like superfamily / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / 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 / Soluble cytochrome b562 / 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 / Relaxin-3 / Relaxin-3 receptor 1
Similarity search - Component
Biological speciesEscherichia coli (E. coli)
Homo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.91 Å
AuthorsChen, Y. / Zhou, Q.T. / Yan, S.Y. / Yan, J.H. / Yang, D.H. / Chen, J. / Wang, M.W.
Funding support China, 3items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)21704064 China
National Natural Science Foundation of China (NSFC)82073904 China
National Natural Science Foundation of China (NSFC)82121005 China
CitationJournal: Commun Biol / Year: 2025
Title: Molecular mechanism underlying non-discriminatory recognition of relaxin-3 by RXFP3 and RXFP4.
Authors: Yan Chen / Qingtong Zhou / Shiyu Yan / Jiahui Yan / Dehua Yang / Jian Chen / Ming-Wei Wang /
Abstract: The human relaxin family peptide receptors RXFP3 and RXFP4 play important physiological roles through interactions with endogenous hormones, relaxin-3 and insulin-like peptide 5 (INSL5). They are ...The human relaxin family peptide receptors RXFP3 and RXFP4 play important physiological roles through interactions with endogenous hormones, relaxin-3 and insulin-like peptide 5 (INSL5). They are implicated in certain neurological and metabolic disorders. While INSL5 only activates RXFP4, relaxin-3 is recognized by both receptors. Here, we report the cryo-electron microscopy structures of RXFP3-G complexes bound by relaxin-3 or a small-molecule dual agonist (compound 4), and relaxin-3 in complex with RXFP4-G, with global resolutions of 2.91 Å, 2.95 Å, and 3.10 Å, respectively. It is found that relaxin-3 adopts a conserved binding conformation within the transmembrane domain (TMD) bundle of RXFP3 and RXFP4, where the C-terminal tip residues of its B chain, R26 and W27, make extensive contacts with conserved receptor residues, thereby activating RXFP3 and RXFP4. Compound 4 mimics these key interactions by binding to both receptors. In contrast, the C-terminal residues composition and TMD-binding angle of INSL5 in RXFP4 differ significantly from that of relaxin-3, ensuring its selectivity for RXFP4. These findings deepen our understanding about the structural basis of ligand recognition and selectivity in this G protein-coupled receptor subfamily.
History
DepositionNov 6, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 13, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
C: Soluble cytochrome b562,Relaxin-3 receptor 1,LgBiT
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
I: Guanine nucleotide-binding protein G(i) subunit alpha-2
S: scFv16
T: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
B: Relaxin-3 B chain
A: Relaxin-3 A chain


Theoretical massNumber of molelcules
Total (without water)199,7607
Polymers199,7607
Non-polymers00
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 GIT

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


Mass: 6089.048 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
#3: Protein Guanine nucleotide-binding protein G(i) subunit alpha-2 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40502.863 Da / Num. of mol.: 1 / Mutation: S47N,G204A,E246A,A327S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI2, GNAI2B / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P04899
#5: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37198.656 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

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Protein/peptide , 2 types, 2 molecules BA

#6: Protein/peptide Relaxin-3 B chain


Mass: 2487.949 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RLN3, INSL7, RXN3, ZINS4, UNQ6188/PRO20213 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8WXF3
#7: Protein/peptide Relaxin-3 A chain


Mass: 2465.845 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RLN3, INSL7, RXN3, ZINS4, UNQ6188/PRO20213 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8WXF3

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Protein / Antibody , 2 types, 2 molecules CS

#1: Protein Soluble cytochrome b562,Relaxin-3 receptor 1,LgBiT / Cytochrome b-562 / RLN3 receptor 1 / G protein-coupled receptor SALPR / G-protein coupled receptor ...Cytochrome b-562 / RLN3 receptor 1 / G protein-coupled receptor SALPR / G-protein coupled receptor GPCR135 / Relaxin family peptide receptor 3 / Somatostatin- and angiotensin-like peptide receptor


Mass: 84607.453 Da / Num. of mol.: 1 / Mutation: M29W, H124I, R128L
Source method: isolated from a genetically manipulated source
Details: BRIL
Source: (gene. exp.) Escherichia coli (E. coli), (gene. exp.) Homo sapiens (human), (gene. exp.) synthetic construct (others)
Gene: cybC, RXFP3, GPCR135, RLN3R1, SALPR / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P0ABE7, UniProt: Q9NSD7
#4: Antibody scFv16


Mass: 26408.492 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Spodoptera frugiperda (fall armyworm)

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Details

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
1Cryo-EM structure of the human relaxin family peptide receptor 3 in complex with relaxin-3 and G proteinCOMPLEXall0RECOMBINANT
2human relaxin-3COMPLEX#6-#71RECOMBINANT
3human relaxin family peptide receptor 3COMPLEX#11RECOMBINANT
4G proteinCOMPLEX#2-#3, #51RECOMBINANT
5scFv16COMPLEX#41RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
33Escherichia coli (E. coli)562
43synthetic construct (others)32630
54Homo sapiens (human)9606
65synthetic construct (others)32630
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: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: OTHER / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 80 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.91 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 364523 / Symmetry type: POINT
RefinementStereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0069484
ELECTRON MICROSCOPYf_angle_d0.68512835
ELECTRON MICROSCOPYf_dihedral_angle_d13.3061289
ELECTRON MICROSCOPYf_chiral_restr0.0461458
ELECTRON MICROSCOPYf_plane_restr0.0051616

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