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- PDB-8zjd: Cryo-EM structure of kisspeptin receptor bound to KP-10 -

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Basic information

Entry
Database: PDB / ID: 8zjd
TitleCryo-EM structure of kisspeptin receptor bound to KP-10
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • KiSS-1 receptor,KiSS-1 receptor,KiSS-1 receptor,KiSS-1 receptor,KiSS-1 receptor, G-protein coupled receptor 54, GPR54, KISS1R
  • kisspeptin-10
  • scFv16
KeywordsMEMBRANE PROTEIN / Cryo-EM / kisspeptin receptor / GPR54 / KISS1R / G proteins
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 / PLC beta mediated events / phospholipase C-activating serotonin receptor signaling pathway / 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 / PLC beta mediated events / phospholipase C-activating serotonin receptor signaling pathway / 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 / photoreceptor outer segment / neuropeptide signaling pathway / postsynaptic cytosol / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex / T cell migration / Adenylate cyclase inhibitory pathway / negative regulation of protein kinase activity / D2 dopamine receptor binding / response to prostaglandin E / enzyme regulator activity / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / cellular response to forskolin / GTPase activator activity / regulation of mitotic spindle organization / Peptide ligand-binding receptors / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / Regulation of insulin secretion / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor binding / negative regulation of insulin secretion / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / response to peptide hormone / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / centriolar satellite / 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 / blood coagulation / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / GDP binding / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / 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 / G protein activity / GTPase binding / Ca2+ pathway / midbody / fibroblast proliferation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / cell cortex / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / nuclear membrane / G alpha (q) signalling events / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / protein stabilization / ciliary basal body
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 / 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(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)
Mus sp. (mice)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.06 Å
AuthorsShen, S. / Liu, H. / Xu, H.E.
Funding support China, 1items
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, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jul 3, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 13, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update
Revision 1.2Jan 15, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
R: KiSS-1 receptor,KiSS-1 receptor,KiSS-1 receptor,KiSS-1 receptor,KiSS-1 receptor, G-protein coupled receptor 54, GPR54, KISS1R
L: kisspeptin-10
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
S: scFv16
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
A: Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(q) subunit alpha


Theoretical massNumber of molelcules
Total (without water)171,5256
Polymers171,5256
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 BGA

#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 38744.371 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
#5: 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
#6: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(q) subunit alpha / Adenylate cyclase-inhibiting G alpha protein / Guanine nucleotide-binding protein alpha-q


Mass: 41312.922 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: fusion protein of Guanine nucleotide-binding protein G(i) subunit alpha-1 and Guanine nucleotide-binding protein G(q) subunit alpha-q.
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1, GNAQ, GAQ / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63096, UniProt: P50148

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

#1: Protein KiSS-1 receptor,KiSS-1 receptor,KiSS-1 receptor,KiSS-1 receptor,KiSS-1 receptor, G-protein coupled receptor 54, GPR54, KISS1R / KiSS-1R / G-protein coupled receptor 54 / G-protein coupled receptor OT7T175 / hOT7T175 / ...KiSS-1R / G-protein coupled receptor 54 / G-protein coupled receptor OT7T175 / hOT7T175 / Hypogonadotropin-1 / Kisspeptins receptor / Metastin receptor


Mass: 55953.941 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KISS1R, AXOR12, GPR54 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q969F8
#2: Protein/peptide kisspeptin-10


Mass: 1375.511 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#4: Antibody scFv16


Mass: 26277.299 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus sp. (mice) / 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

ComponentName: Cryo-EM structure of kisspeptin receptor in complex with G proteins
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo Sapiens (human)
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: FEI TITAN 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

CTF correctionType: NONE
3D reconstructionResolution: 3.06 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 199591 / Symmetry type: POINT

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