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- EMDB-60142: Cryo-EM structure of kisspeptin receptor bound to TAK-448 -

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Entry
Database: EMDB / ID: EMD-60142
TitleCryo-EM structure of kisspeptin receptor bound to TAK-448
Map data
Sample
  • Complex: cryo-EM structure of kisspeptin receptor in complex with G proteins
    • 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
    • Protein or peptide: KiSS-1 receptor
    • Protein or peptide: scFv16
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(q) subunit alpha
  • Protein or peptide: ACE-DTY-HYP-ASN-THR-PHE-XZA-LEU-NMM-TRP-NH2
KeywordsCryo-EM / kisspeptin receptor / GPR54 / G proteins / MEMBRANE PROTEIN / KISS1R
Function / homology
Function and homology information


Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / neuropeptide receptor activity / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway / phospholipase C-activating serotonin receptor signaling pathway / PLC beta mediated events / entrainment of circadian clock / regulation of platelet activation / G protein-coupled peptide receptor activity / regulation of canonical Wnt signaling pathway ...Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / neuropeptide receptor activity / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway / phospholipase C-activating serotonin receptor signaling pathway / PLC beta mediated events / entrainment of circadian clock / regulation of platelet activation / G protein-coupled peptide receptor activity / regulation of canonical Wnt signaling pathway / glutamate receptor signaling pathway / phototransduction, visible light / postsynaptic cytosol / photoreceptor outer segment / neuropeptide signaling pathway / positive regulation of protein localization to cell cortex / Adenylate cyclase inhibitory pathway / T cell migration / D2 dopamine receptor binding / enzyme regulator activity / response to prostaglandin E / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / cellular response to forskolin / regulation of mitotic spindle organization / GTPase activator activity / Peptide ligand-binding receptors / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / negative regulation of protein kinase activity / Regulation of insulin secretion / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / response to peptide hormone / G-protein beta/gamma-subunit complex binding / centriolar satellite / 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 / blood coagulation / GDP binding / 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) / G protein activity / GTPase binding / Ca2+ pathway / retina development in camera-type eye / midbody / cell cortex / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / G alpha (i) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / nuclear membrane / G alpha (q) signalling events / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / protein stabilization / ciliary basal body / cilium / G protein-coupled receptor signaling pathway
Similarity search - Function
KiSS-1 peptide receptor / G-protein alpha subunit, group Q / 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. ...KiSS-1 peptide receptor / G-protein alpha subunit, group Q / 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 / 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 / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Guanine nucleotide-binding protein G(q) subunit alpha / 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(i) subunit alpha-1 / KiSS-1 receptor
Similarity search - Component
Biological speciesHomo Sapiens (human) / Homo sapiens (human) / Mus sp. (mice) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.07 Å
AuthorsShen S / Liu H / Xu HE
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Cell Rep / Year: 2024
Title: Structural basis for hormone recognition and distinctive Gq protein coupling by the kisspeptin receptor.
Authors: Shiyi Shen / Dongxue Wang / Heng Liu / Xinheng He / Yinglong Cao / Juanhua Chen / Shujie Li / Xi Cheng / H Eric Xu / Jia Duan /
Abstract: Kisspeptin signaling through its G protein-coupled receptor, KISS1R, plays an indispensable role in regulating reproduction via the hypothalamic-pituitary-gonadal axis. Dysregulation of this pathway ...Kisspeptin signaling through its G protein-coupled receptor, KISS1R, plays an indispensable role in regulating reproduction via the hypothalamic-pituitary-gonadal axis. Dysregulation of this pathway underlies severe disorders like infertility and precocious puberty. Here, we present cryo-EM structures of KISS1R bound to the endogenous agonist kisspeptin-10 and a synthetic analog TAK-448. These structures reveal pivotal interactions between peptide ligands and KISS1R extracellular loops for receptor activation. Both peptides exhibit a conserved binding mode, unveiling their common activation mechanism. Intriguingly, KISS1R displays a distinct 40° angular deviation in its intracellular TM6 region compared to other G-coupled receptors, enabling distinct interactions with G. This study reveals the molecular intricacies governing ligand binding and activation of KISS1R, while highlighting its exceptional ability to couple with G. Our findings pave the way for structure-guided design of therapeutics targeting this physiologically indispensable receptor.
History
DepositionMay 14, 2024-
Header (metadata) releaseJul 3, 2024-
Map releaseJul 3, 2024-
UpdateJan 15, 2025-
Current statusJan 15, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_60142.png

Downloads & links

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Map

FileDownload / File: emd_60142.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 256 pix.
= 186.88 Å		0.73 Å/pix.
x 256 pix.
= 186.88 Å		0.73 Å/pix.
x 256 pix.
= 186.88 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.73 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.25
Minimum - Maximum-1.4820471 - 2.0939739
Average (Standard dev.)0.0065851677 (±0.069178514)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 186.88 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_60142_msk_1.map
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Half map: #2

Fileemd_60142_half_map_1.map
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Half map: #1

Fileemd_60142_half_map_2.map
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Sample components

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Entire : cryo-EM structure of kisspeptin receptor in complex with G proteins

EntireName: cryo-EM structure of kisspeptin receptor in complex with G proteins
Components
  • Complex: cryo-EM structure of kisspeptin receptor in complex with G proteins
    • 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
    • Protein or peptide: KiSS-1 receptor
    • Protein or peptide: scFv16
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(q) subunit alpha
  • Protein or peptide: ACE-DTY-HYP-ASN-THR-PHE-XZA-LEU-NMM-TRP-NH2

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Supramolecule #1: cryo-EM structure of kisspeptin receptor in complex with G proteins

SupramoleculeName: cryo-EM structure of kisspeptin receptor in complex with G proteins
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #2-#5, #1
Source (natural)Organism: Homo Sapiens (human)

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Macromolecule #1: Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine n...

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(q) subunit alpha
type: protein_or_peptide / ID: 1
Details: fusion protein of Guanine nucleotide-binding protein G(i) subunit alpha-1 and Guanine nucleotide-binding protein G(q) subunit alpha-q.
Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.312922 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGCTLSAEDK AAVERSKMID RNLREDGERS RRELKLLLLG TGESGKSTFI KQMRIIHGSG YSDEDKRGFT KLVYQNIFTA MQAMIRAMD TLKIPYKYEH NKAHAQLVRE VDVEKVSAFE NPYVDAIKSL WNDPGIQECY DRRREYQLSD STKYYLNDLD R VADPAYLP ...String:
MGCTLSAEDK AAVERSKMID RNLREDGERS RRELKLLLLG TGESGKSTFI KQMRIIHGSG YSDEDKRGFT KLVYQNIFTA MQAMIRAMD TLKIPYKYEH NKAHAQLVRE VDVEKVSAFE NPYVDAIKSL WNDPGIQECY DRRREYQLSD STKYYLNDLD R VADPAYLP TQQDVLRVRV PTTGIIEYPF DLQSVIFRMV DVGAQRSERR KWIHCFENVT SIMFLVALSE YDQVLVESDN EN RMEESKA LFRTIITYPW FQNSSVILFL NKKDLLEEKI MYSHLVDYFP EYDGPQRDAQ AAREFILKMF VDLNPDSDKI IYS HFTCST DTENIRFVFA AVKDTILQLN LKEYNLV

UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(q) subunit alpha

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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 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 38.744371 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MHHHHHHGSL LQSELDQLRQ EAEQLKNQIR DARKACADAT LSQITNNIDP VGRIQMRTRR TLRGHLAKIY AMHWGTDSRL LVSASQDGK LIIWDSYTTN KVHAIPLRSS WVMTCAYAPS GNYVACGGLD NICSIYNLKT REGNVRVSRE LAGHTGYLSC C RFLDDNQI ...String:
MHHHHHHGSL LQSELDQLRQ EAEQLKNQIR DARKACADAT LSQITNNIDP VGRIQMRTRR TLRGHLAKIY AMHWGTDSRL LVSASQDGK LIIWDSYTTN KVHAIPLRSS WVMTCAYAPS GNYVACGGLD NICSIYNLKT REGNVRVSRE LAGHTGYLSC C RFLDDNQI VTSSGDTTCA LWDIETGQQT TTFTGHTGDV MSLSLAPDTR LFVSGACDAS AKLWDVREGM CRQTFTGHES DI NAICFFP NGNAFATGSD DATCRLFDLR ADQELMTYSH DNIICGITSV SFSKSGRLLL AGYDDFNCNV WDALKADRAG VLA GHDNRV SCLGVTDDGM AVATGSWDSF LKIWN

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 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
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: KiSS-1 receptor

MacromoleculeName: KiSS-1 receptor / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 42.747094 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MHTVATSGPN ASWGAPANAS GCPGCGANAS DGPVPSPRAV DAWLVPLFFA ALMLLGLVGN SLVIYVICRH KPMRTVTNFY IANLAATDV TFLLCCVPFT ALLYPLPGWV LGDFMCKFVN YIQQVSVQAT CWTLTAMSVD RWYVTVFPLR ALHRRTPRLA L AVSLSIWV ...String:
MHTVATSGPN ASWGAPANAS GCPGCGANAS DGPVPSPRAV DAWLVPLFFA ALMLLGLVGN SLVIYVICRH KPMRTVTNFY IANLAATDV TFLLCCVPFT ALLYPLPGWV LGDFMCKFVN YIQQVSVQAT CWTLTAMSVD RWYVTVFPLR ALHRRTPRLA L AVSLSIWV GSAAVSAPVL ALHRLSPGPR AYCSEAFPSR ALERAFALYN LLALYLLPLL ATCACYAAML RHLGRVAVRP AP ADSALQG QVLAERAGAV RAKVSRLVAA VVLLFAACWG PIQLFLVLQA LGPAGSWHPR SYAAYALKTW AHCMSYSNSA LNP LLYAFL GSHFRQAFRR VCPCAPRRPR RPRRPGPSDP AAPHAELLRL GSHPAPARAQ KPGSSGLAAR GLCVLGEDNA PL

UniProtKB: KiSS-1 receptor

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Macromolecule #5: scFv16

MacromoleculeName: scFv16 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus sp. (mice)
Molecular weightTheoretical: 26.277299 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS AGGGGSGGGG SGGGGSADIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...String:
VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS AGGGGSGGGG SGGGGSADIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL

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Macromolecule #6: ACE-DTY-HYP-ASN-THR-PHE-XZA-LEU-NMM-TRP-NH2

MacromoleculeName: ACE-DTY-HYP-ASN-THR-PHE-XZA-LEU-NMM-TRP-NH2 / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 1.20835 KDa
SequenceString:
(ACE)(DTY)(HYP)NTF(XZA)L(NMM)W (NH2)

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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

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: DARK FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.07 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 111547
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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