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- EMDB-26004: Cryo-EM map of the full-length relaxin receptor RXFP1 in complex ... -

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Entry
Database: EMDB / ID: EMD-26004
TitleCryo-EM map of the full-length relaxin receptor RXFP1 in complex with heterotrimeric Gs
Map dataRelaxin receptor RXFP1 in complex with heterotrimeric Gs
Sample
  • Complex: Complex of the relaxin receptor RXFP1 and heterotrimeric Gs
    • Complex: Relaxin receptor 1, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
      • Protein or peptide: Relaxin receptor 1, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short fusion
    • Complex: 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
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Complex: Camelid antibody VHH fragment Nb35
      • Protein or peptide: Camelid antibody VHH fragment Nb35
KeywordsGPCR / Complex / Signaling / Relaxin / MEMBRANE PROTEIN
Function / homology
Function and homology information


lung connective tissue development / nipple morphogenesis / Relaxin receptors / parturition / myofibroblast differentiation / hormone binding / G protein-coupled peptide receptor activity / PKA activation in glucagon signalling / hair follicle placode formation / developmental growth ...lung connective tissue development / nipple morphogenesis / Relaxin receptors / parturition / myofibroblast differentiation / hormone binding / G protein-coupled peptide receptor activity / PKA activation in glucagon signalling / hair follicle placode formation / developmental growth / intracellular transport / D1 dopamine receptor binding / positive regulation of cAMP-mediated signaling / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / adenylate cyclase activator activity / hormone-mediated signaling pathway / extracellular matrix organization / trans-Golgi network membrane / G protein-coupled receptor activity / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / bone development / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / cognition / photoreceptor disc membrane / platelet aggregation / Adrenaline,noradrenaline inhibits insulin secretion / positive regulation of GTPase activity / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / sensory perception of smell / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / GTPase binding / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / positive regulation of cold-induced thermogenesis / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / cell population proliferation / Ras protein signal transduction / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / GTP binding / signal transduction / extracellular exosome / membrane / metal ion binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Relaxin receptor / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A, conserved site / LDL-receptor class A (LDLRA) domain signature. / LDL-receptor class A (LDLRA) domain profile. / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A repeat / LDL receptor-like superfamily / Leucine-rich repeat, SDS22-like subfamily / G-protein alpha subunit, group S ...Relaxin receptor / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A, conserved site / LDL-receptor class A (LDLRA) domain signature. / LDL-receptor class A (LDLRA) domain profile. / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A repeat / LDL receptor-like superfamily / Leucine-rich repeat, SDS22-like subfamily / G-protein alpha subunit, group S / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. / Leucine-rich repeat / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / Leucine-rich repeat domain superfamily / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / 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. / WD domain, G-beta repeat / 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)/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 short / Relaxin receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human) / Lama glama (llama)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.2 Å
AuthorsErlandson SC / Rawson S / Kruse AC
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)5F32GM128233-03 United States
Other private United States
CitationJournal: Nat Chem Biol / Year: 2023
Title: The relaxin receptor RXFP1 signals through a mechanism of autoinhibition.
Authors: Sarah C Erlandson / Shaun Rawson / James Osei-Owusu / Kelly P Brock / Xinyue Liu / Joao A Paulo / Julian Mintseris / Steven P Gygi / Debora S Marks / Xiaojing Cong / Andrew C Kruse /
Abstract: The relaxin family peptide receptor 1 (RXFP1) is the receptor for relaxin-2, an important regulator of reproductive and cardiovascular physiology. RXFP1 is a multi-domain G protein-coupled receptor ...The relaxin family peptide receptor 1 (RXFP1) is the receptor for relaxin-2, an important regulator of reproductive and cardiovascular physiology. RXFP1 is a multi-domain G protein-coupled receptor (GPCR) with an ectodomain consisting of a low-density lipoprotein receptor class A (LDLa) module and leucine-rich repeats. The mechanism of RXFP1 signal transduction is clearly distinct from that of other GPCRs, but remains very poorly understood. In the present study, we determine the cryo-electron microscopy structure of active-state human RXFP1, bound to a single-chain version of the endogenous agonist relaxin-2 and the heterotrimeric G protein. Evolutionary coupling analysis and structure-guided functional experiments reveal that RXFP1 signals through a mechanism of autoinhibition. Our results explain how an unusual GPCR family functions, providing a path to rational drug development targeting the relaxin receptors.
History
DepositionJan 20, 2022-
Header (metadata) releaseMay 3, 2023-
Map releaseMay 3, 2023-
UpdateAug 9, 2023-
Current statusAug 9, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26004.png

Downloads & links

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Map

FileDownload / File: emd_26004.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationRelaxin receptor RXFP1 in complex with heterotrimeric Gs
Voxel sizeX=Y=Z: 1.06 Å
Density
Contour LevelBy AUTHOR: 0.0143
Minimum - Maximum-0.07328965 - 0.1274189
Average (Standard dev.)0.0002017556 (±0.0029537142)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 305.27997 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Relaxin receptor RXFP1 in complex with heterotrimeric Gs

Fileemd_26004_additional_1.map
AnnotationRelaxin receptor RXFP1 in complex with heterotrimeric Gs
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Relaxin receptor RXFP1 in complex with heterotrimeric Gs

Fileemd_26004_half_map_1.map
AnnotationRelaxin receptor RXFP1 in complex with heterotrimeric Gs
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Relaxin receptor RXFP1 in complex with heterotrimeric Gs

Fileemd_26004_half_map_2.map
AnnotationRelaxin receptor RXFP1 in complex with heterotrimeric Gs
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of the relaxin receptor RXFP1 and heterotrimeric Gs

EntireName: Complex of the relaxin receptor RXFP1 and heterotrimeric Gs
Components
  • Complex: Complex of the relaxin receptor RXFP1 and heterotrimeric Gs
    • Complex: Relaxin receptor 1, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
      • Protein or peptide: Relaxin receptor 1, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short fusion
    • Complex: 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
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Complex: Camelid antibody VHH fragment Nb35
      • Protein or peptide: Camelid antibody VHH fragment Nb35

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Supramolecule #1: Complex of the relaxin receptor RXFP1 and heterotrimeric Gs

SupramoleculeName: Complex of the relaxin receptor RXFP1 and heterotrimeric Gs
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Molecular weightTheoretical: 180 KDa

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Supramolecule #2: Relaxin receptor 1, Guanine nucleotide-binding protein G(s) subun...

SupramoleculeName: Relaxin receptor 1, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,...

SupramoleculeName: 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
type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#3
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #4: Camelid antibody VHH fragment Nb35

SupramoleculeName: Camelid antibody VHH fragment Nb35 / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #4
Source (natural)Organism: Lama glama (llama)

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Macromolecule #1: Relaxin receptor 1, Guanine nucleotide-binding protein G(s) subun...

MacromoleculeName: Relaxin receptor 1, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short fusion
type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DYKDDDDGGS LEVLFQGPGG SQDVKCSLGY FPCGNITKCL PQLLHCNGVD DCGNQADEDN CGDNNGWSLQ FDKYFASYYK MTSQYPFEAE TPECLVGSVP VQCLCQGLEL DCDETNLRAV PSVSSNVTAM SLQWNLIRKL PPDCFKNYHD LQKLYLQNNK ITSISIYAFR ...String:
DYKDDDDGGS LEVLFQGPGG SQDVKCSLGY FPCGNITKCL PQLLHCNGVD DCGNQADEDN CGDNNGWSLQ FDKYFASYYK MTSQYPFEAE TPECLVGSVP VQCLCQGLEL DCDETNLRAV PSVSSNVTAM SLQWNLIRKL PPDCFKNYHD LQKLYLQNNK ITSISIYAFR GLNSLTKLYL SHNRITFLKP GVFEDLHRLE WLIIEDNHLS RISPPTFYGL NSLILLVLMN NVLTRLPDKP LCQHMPRLHW LDLEGNHIHN LRNLTFISCS NLTVLVMRKN KINHLNENTF APLQKLDELD LGSNKIENLP PLIFKDLKEL SQLNLSYNPI QKIQANQFDY LVKLKSLSLE GIEISNIQQR MFRPLMNLSH IYFKKFQYCG YAPHVRSCKP NTDGISSLEN LLASIIQRVF VWVVSAVTCF GNIFVICMRP YIRSENKLYA MSIISLCCAD CLMGIYLFVI GGFDLKFRGE YNKHAQLWME STHCQLVGSL AILSTEVSVL LLTFLTLEKY ICIVYPFRCV RPGKCRTITV LILIWITGFI VAFIPLSNKE FFKNYYGTNG VCFPLHSEDT ESIGAQIYSV AIFLGINLAA FIIIVFSYGS MFYSVHQSAI TATEIRNQVK KEMILAKRFF FIVFTDALCW IPIFVVKFLS LLQVEIPGTI TSWVVIFILP INSALNPILY TLTTRPFKEM IHRFWYNYRQ RKSMDSKGQK TYAPSFIWVE MWPLQEMPPE LMKPDLNSKT EDQRNEEKAQ REANKKIEKQ LQKDKQVYRA THRLLLLGAD NSGKSTIVKQ MRIYHGGSGG SGGTSGIFET KFQVDKVNFH MFDVGGQRDE RRKWIQCFND VTAIIFVVDS SDYNRLQEAL NLFKSIWNNR WLRTISVILF LNKQDLLAEK VLAGKSKIED YFPEFARYTT PEDATPEPGE DPRVTRAKYF IRDEFLRIST ASGDGRHYCY PHFTCAVDTE NARRIFNDCR DIIQRMHLRQ YELL

UniProtKB: Relaxin receptor 1, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short

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Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MHHHHHHGSS GSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNKV HAIPLRSSWV MTCAYAPSGN YVACGGLDNI CSIYNLKTRE GNVRVSRELA GHTGYLSCCR FLDDNQIVTS ...String:
MHHHHHHGSS GSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNKV HAIPLRSSWV MTCAYAPSGN YVACGGLDNI CSIYNLKTRE GNVRVSRELA GHTGYLSCCR FLDDNQIVTS SGDTTCALWD IETGQQTTTF TGHTGDVMSL SLAPDTRLFV SGACDASAKL WDVREGMCRQ TFTGHESDIN AICFFPNGNA FATGSDDATC RLFDLRADQE LMTYSHDNII CGITSVSFSK SGRLLLAGYD DFNCNVWDAL KADRAGVLAG HDNRVSCLGV TDDGMAVATG SWDSFLKIWN

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

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

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Macromolecule #4: Camelid antibody VHH fragment Nb35

MacromoleculeName: Camelid antibody VHH fragment Nb35 / type: protein_or_peptide / ID: 4 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
QVQLQESGGG LVQPGGSLRL SCAASGFTFS NYKMNWVRQA PGKGLEWVSD ISQSGASISY TGSVKGRFTI SRDNAKNTLY LQMNSLKPED TAVYYCARCP APFTRDCFDV TSTTYAYRGQ GTQVTVSSLE VLFQGPGHHH HHHHHGSEDQ VDPRLIDGK

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.2 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 283.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.3000000000000003 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 81000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 52.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 15826542
Startup modelType of model: OTHER / Details: Ab initio model generated in RELION
Initial angle assignmentType: RANDOM ASSIGNMENT / Software - Name: RELION (ver. 3.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.1)
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 4.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 45146

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