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- PDB-8xgu: a peptide receptor complex structure -

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Basic information

Entry
Database: PDB / ID: 8xgu
Titlea peptide receptor complex structure
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • KiSS-1 receptor
  • TAK448
  • scfv16
KeywordsSTRUCTURAL PROTEIN/IMMUNE SYSTEM / a peptide related GPCR-Gq complex / STRUCTURAL PROTEIN / STRUCTURAL PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


neuropeptide receptor activity / G protein-coupled peptide receptor activity / neuropeptide signaling pathway / positive regulation of protein localization to cell cortex / Adenylate cyclase inhibitory pathway / T cell migration / D2 dopamine receptor binding / response to prostaglandin E / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity ...neuropeptide receptor activity / G protein-coupled peptide receptor activity / neuropeptide signaling pathway / positive regulation of protein localization to cell cortex / Adenylate cyclase inhibitory pathway / T cell migration / D2 dopamine receptor binding / 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 / Peptide ligand-binding receptors / 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 / 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 / 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 / G alpha (q) signalling events / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / ciliary basal body / cilium / G protein-coupled receptor signaling pathway / lysosomal membrane / cell division / GTPase activity / intracellular membrane-bounded organelle / synapse / centrosome / protein-containing complex binding / GTP binding / nucleolus / cell surface / magnesium ion binding / Golgi apparatus / signal transduction / extracellular exosome / nucleoplasm / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
KiSS-1 peptide receptor / 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 ...KiSS-1 peptide receptor / 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(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)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsWu, Z. / Du, Y. / Chen, G.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Sci Adv / Year: 2024
Title: Structural basis for the ligand recognition and G protein subtype selectivity of kisspeptin receptor.
Authors: Zhangsong Wu / Geng Chen / Chen Qiu / Xiaoyi Yan / Lezhi Xu / Shirui Jiang / Jun Xu / Runyuan Han / Tingyi Shi / Yiming Liu / Wei Gao / Qian Wang / Jiancheng Li / Fang Ye / Xin Pan / Zhiyi ...Authors: Zhangsong Wu / Geng Chen / Chen Qiu / Xiaoyi Yan / Lezhi Xu / Shirui Jiang / Jun Xu / Runyuan Han / Tingyi Shi / Yiming Liu / Wei Gao / Qian Wang / Jiancheng Li / Fang Ye / Xin Pan / Zhiyi Zhang / Peiruo Ning / Binghao Zhang / Jing Chen / Yang Du /
Abstract: Kisspeptin receptor (KISS1R), belonging to the class A peptide-GPCR family, plays a key role in the regulation of reproductive physiology after stimulation by kisspeptin and is regarded as an ...Kisspeptin receptor (KISS1R), belonging to the class A peptide-GPCR family, plays a key role in the regulation of reproductive physiology after stimulation by kisspeptin and is regarded as an attractive drug target for reproductive diseases. Here, we demonstrated that KISS1R can couple to the G pathway besides the well-known G pathway. We further resolved the cryo-electron microscopy (cryo-EM) structure of KISS1R-G and KISS1R-G complexes bound to the synthetic agonist TAK448 and structure of KISS1R-G complex bound to the endogenous agonist KP54. The high-resolution structures provided clear insights into mechanism of KISS1R recognition by its ligand and can facilitate the design of targeted drugs with high affinity to improve treatment effects. Moreover, the structural and functional analyses indicated that conformational differences in the extracellular loops (ECLs), intracellular loops (ICLs) of the receptor, and the "wavy hook" of the Gα subunit may account for the specificity of G protein coupling for KISS1R signaling.
History
DepositionDec 15, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 30, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: KiSS-1 receptor
C: Guanine nucleotide-binding protein G(i) subunit alpha-1
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
S: scfv16
E: TAK448


Theoretical massNumber of molelcules
Total (without water)158,8506
Polymers158,8506
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 CBG

#2: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40153.672 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1
Production host: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
References: UniProt: P63096
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 39286.891 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1
Production host: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
References: UniProt: P62873
#4: 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 aff. frugiperda 1 BOLD-2017 (butterflies/moths)
References: UniProt: P59768

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

#1: Protein KiSS-1 receptor / 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: 42631.965 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: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
References: UniProt: Q969F8
#5: Antibody scfv16


Mass: 27707.885 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
Production host: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
#6: Protein/peptide TAK448


Mass: 1208.350 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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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
1kp54-KISS1R-Gq-scfv16COMPLEXall0RECOMBINANT
2KISS1RCOMPLEX#1, #61RECOMBINANT
3Guanine 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,Guanine nucleotide-binding protein G(i) subunit alpha-1COMPLEX#2-#41RECOMBINANT
4scfv16COMPLEX#51RECOMBINANT
Molecular weightValue: 0.13 MDa / Experimental value: YES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
43Homo sapiens (human)9606
54Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)2449148
32Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)2449148
43Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)2449148
54Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)2449148
Buffer solutionpH: 7.5
SpecimenConc.: 5 mg/ml / Embedding 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: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 1.13 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.4.1particle selection
4cryoSPARC4.4.1CTF correction
10cryoSPARC4.4.1initial Euler assignment
11cryoSPARC4.4.1final Euler assignment
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1018641
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1018641 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0038991
ELECTRON MICROSCOPYf_angle_d0.6112195
ELECTRON MICROSCOPYf_dihedral_angle_d13.2021257
ELECTRON MICROSCOPYf_chiral_restr0.0431379
ELECTRON MICROSCOPYf_plane_restr0.0041544

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