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- PDB-7yk7: Cryo-EM structure of the DC591053-bound human relaxin family pept... -

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Basic information

Entry
Database: PDB / ID: 7yk7
TitleCryo-EM structure of the DC591053-bound human relaxin family peptide receptor 4 (RXFP4)-Gi complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Relaxin-3 receptor 2
  • scFv16
KeywordsSTRUCTURAL PROTEIN / human relaxin family peptide receptor 4 / G protein-coupled receptor / ligand recognition
Function / homology
Function and homology information


Relaxin receptors / positive regulation of feeding behavior / 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 ...Relaxin receptors / positive regulation of feeding behavior / 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 / 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 / gamma-aminobutyric acid signaling pathway / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / neuronal dense core vesicle / negative regulation of apoptotic signaling pathway / regulation of calcium ion transport / neuropeptide signaling pathway / Adenylate cyclase inhibitory pathway / positive regulation of vascular associated smooth muscle cell proliferation / response to nutrient / hippocampal mossy fiber to CA3 synapse / positive regulation of superoxide anion generation / Regulation of insulin secretion / G protein-coupled receptor binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / 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 / adenylate cyclase-activating G protein-coupled 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 / 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 / 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) / cell body / GTPase binding / Ca2+ pathway / retina development in camera-type eye / midbody / 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
Similarity search - Function
Angiotensin II receptor family / : / G-protein alpha subunit, group I / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. ...Angiotensin II receptor family / : / G-protein alpha subunit, group I / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / 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 / 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. / WD domain, G-beta repeat / 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 / Immunoglobulins / Immunoglobulin-like / Sandwich / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
Chem-IYM / Guanine nucleotide-binding protein G(i) subunit alpha-2 / 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 / Relaxin-3 receptor 2
Similarity search - Component
Biological speciesBos taurus (domestic cattle)
Homo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.75 Å
AuthorsChen, Y. / Zhou, Q.T. / Wang, J. / Xu, Y.W. / Wang, Y. / Yan, J.H. / Wang, Y.B. / Zhu, Q. / Zhao, F.H. / Li, C.H. ...Chen, Y. / Zhou, Q.T. / Wang, J. / Xu, Y.W. / Wang, Y. / Yan, J.H. / Wang, Y.B. / Zhu, Q. / Zhao, F.H. / Li, C.H. / Chen, C.W. / Cai, X.Q. / Bathgate, R.A.D. / Shen, C. / Xu, H.E. / Yang, D.H. / Liu, H. / Wang, M.W.
Funding support China, 11items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81872915 China
National Natural Science Foundation of China (NSFC)82073904 China
National Natural Science Foundation of China (NSFC)82120105 China
National Natural Science Foundation of China (NSFC)81973373 China
National Natural Science Foundation of China (NSFC)82130105 China
National Natural Science Foundation of China (NSFC)21704064 China
Other government2021ZD0203400
Other government2018YFA0507000
Other governmentZDKJ2021028
Other government21JC1401600
Other government1135837
CitationJournal: Nat Commun / Year: 2023
Title: Ligand recognition mechanism of the human relaxin family peptide receptor 4 (RXFP4).
Authors: Yan Chen / Qingtong Zhou / Jiang Wang / Youwei Xu / Yun Wang / Jiahui Yan / Yibing Wang / Qi Zhu / Fenghui Zhao / Chenghao Li / Chuan-Wei Chen / Xiaoqing Cai / Ross A D Bathgate / Chun Shen ...Authors: Yan Chen / Qingtong Zhou / Jiang Wang / Youwei Xu / Yun Wang / Jiahui Yan / Yibing Wang / Qi Zhu / Fenghui Zhao / Chenghao Li / Chuan-Wei Chen / Xiaoqing Cai / Ross A D Bathgate / Chun Shen / H Eric Xu / Dehua Yang / Hong Liu / Ming-Wei Wang /
Abstract: Members of the insulin superfamily regulate pleiotropic biological processes through two types of target-specific but structurally conserved peptides, insulin/insulin-like growth factors and ...Members of the insulin superfamily regulate pleiotropic biological processes through two types of target-specific but structurally conserved peptides, insulin/insulin-like growth factors and relaxin/insulin-like peptides. The latter bind to the human relaxin family peptide receptors (RXFPs). Here, we report three cryo-electron microscopy structures of RXFP4-G protein complexes in the presence of the endogenous ligand insulin-like peptide 5 (INSL5) or one of the two small molecule agonists, compound 4 and DC591053. The B chain of INSL5 adopts a single α-helix that penetrates into the orthosteric pocket, while the A chain sits above the orthosteric pocket, revealing a peptide-binding mode previously unknown. Together with mutagenesis and functional analyses, the key determinants responsible for the peptidomimetic agonism and subtype selectivity were identified. Our findings not only provide insights into ligand recognition and subtype selectivity among class A G protein-coupled receptors, but also expand the knowledge of signaling mechanisms in the insulin superfamily.
History
DepositionJul 21, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 1, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
I: Guanine nucleotide-binding protein G(i) subunit alpha-2
R: Relaxin-3 receptor 2
S: scFv16
T: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)154,3596
Polymers153,8655
Non-polymers4941
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules GIT

#1: 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.) Bos taurus (domestic cattle) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63212
#2: 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: 37915.496 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 / Antibody / Non-polymers , 3 types, 3 molecules RS

#3: Protein Relaxin-3 receptor 2 / RLN3 receptor 2 / G-protein coupled receptor 100 / G-protein coupled receptor GPCR142 / Insulin- ...RLN3 receptor 2 / G-protein coupled receptor 100 / G-protein coupled receptor GPCR142 / Insulin-like peptide INSL5 receptor / Relaxin family peptide receptor 4


Mass: 41177.270 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RXFP4, GPCR142, GPR100, RLN3R2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8TDU9
#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)
#6: Chemical ChemComp-IYM / [(1S)-7-ethoxy-6-methoxy-1-[2-(5-methoxy-1H-indol-3-yl)ethyl]-3,4-dihydro-1H-isoquinolin-2-yl]-morpholin-4-yl-methanone


Mass: 493.595 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H35N3O5 / 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
1Cryo-EM structure of the human relaxin family peptide receptor 4 in complex with DC591053 and G proteinCOMPLEX#1-#50RECOMBINANT
2relaxin family peptide receptor 4COMPLEX#31RECOMBINANT
3G proteinCOMPLEX#1-#2, #51MULTIPLE SOURCES
4scFv16COMPLEX#41RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Bos taurus (domestic cattle)9913
33Homo sapiens (human)9606
44synthetic construct (others)32630
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Spodoptera frugiperda (fall armyworm)7108
23Spodoptera frugiperda (fall armyworm)7108
34Spodoptera frugiperda (fall armyworm)7108
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: FEI TITAN KRIOS
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

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.75 Å / Resolution method: DIFFRACTION PATTERN/LAYERLINES / Num. of particles: 225327 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0058954
ELECTRON MICROSCOPYf_angle_d0.68912153
ELECTRON MICROSCOPYf_dihedral_angle_d6.8061224
ELECTRON MICROSCOPYf_chiral_restr0.0471380
ELECTRON MICROSCOPYf_plane_restr0.0041533

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