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- PDB-8w8s: Cryo-EM structure of the AA14-bound GPR101 complex -

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Basic information

Entry
Database: PDB / ID: 8w8s
TitleCryo-EM structure of the AA14-bound GPR101 complex
ComponentsProbable G-protein coupled receptor 101
KeywordsMEMBRANE PROTEIN / GPCR / orphan receptor / GPR101 / constitutive activity / cryo-EM / structural protein
Function / homology
Function and homology information


adenylate cyclase-activating adrenergic receptor signaling pathway / G protein-coupled receptor activity / receptor complex / plasma membrane
Similarity search - Function
G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family)
Similarity search - Domain/homology
Chem-U7D / Probable G-protein coupled receptor 101
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsSun, J.P. / Yu, X. / Gao, N. / Yang, F. / Wang, J.Y. / Yang, Z. / Guan, Y. / Wang, G.P.
Funding support China, 5items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31725007 China
National Natural Science Foundation of China (NSFC)32130055 China
National Natural Science Foundation of China (NSFC)92057121 China
National Science Foundation (NSF, China)81825022 China
National Science Foundation (NSF, China)82225011 China
CitationJournal: Nat Chem Biol / Year: 2024
Title: Structure of GPR101-Gs enables identification of ligands with rejuvenating potential.
Authors: Zhao Yang / Jun-Yan Wang / Fan Yang / Kong-Kai Zhu / Guo-Peng Wang / Ying Guan / Shang-Lei Ning / Yan Lu / Yu Li / Chao Zhang / Yuan Zheng / Shu-Hua Zhou / Xin-Wen Wang / Ming-Wei Wang / ...Authors: Zhao Yang / Jun-Yan Wang / Fan Yang / Kong-Kai Zhu / Guo-Peng Wang / Ying Guan / Shang-Lei Ning / Yan Lu / Yu Li / Chao Zhang / Yuan Zheng / Shu-Hua Zhou / Xin-Wen Wang / Ming-Wei Wang / Peng Xiao / Fan Yi / Cheng Zhang / Peng-Ju Zhang / Fei Xu / Bao-Hua Liu / Hua Zhang / Xiao Yu / Ning Gao / Jin-Peng Sun /
Abstract: GPR101 is an orphan G protein-coupled receptor actively participating in energy homeostasis. Here we report the cryo-electron microscopy structure of GPR101 constitutively coupled to Gs heterotrimer, ...GPR101 is an orphan G protein-coupled receptor actively participating in energy homeostasis. Here we report the cryo-electron microscopy structure of GPR101 constitutively coupled to Gs heterotrimer, which reveals unique features of GPR101, including the interaction of extracellular loop 2 within the 7TM bundle, a hydrophobic chain packing-mediated activation mechanism and the structural basis of disease-related mutants. Importantly, a side pocket is identified in GPR101 that facilitates in silico screening to identify four small-molecule agonists, including AA-14. The structure of AA-14-GPR101-Gs provides direct evidence of the AA-14 binding at the side pocket. Functionally, AA-14 partially restores the functions of GH/IGF-1 axis and exhibits several rejuvenating effects in wild-type mice, which are abrogated in Gpr101-deficient mice. In summary, we provide a structural basis for the constitutive activity of GPR101. The structure-facilitated identification of GPR101 agonists and functional analysis suggest that targeting this orphan receptor has rejuvenating potential.
History
DepositionSep 4, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jan 3, 2024Provider: repository / Type: Initial release
Revision 1.1Apr 10, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
R: Probable G-protein coupled receptor 101
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,3983
Polymers56,7751
Non-polymers6232
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Probable G-protein coupled receptor 101


Mass: 56774.926 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GPR101 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q96P66
#2: Chemical ChemComp-U7D / 1-(4-methylpyridin-2-yl)-3-[3-(trifluoromethyl)phenyl]thiourea / CHEMBL2134995


Mass: 311.325 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H12F3N3S
Has ligand of interestN

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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 the AA14-bound GPR101-Gs complex / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
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: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1200 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 3646024 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0022353
ELECTRON MICROSCOPYf_angle_d0.6473222
ELECTRON MICROSCOPYf_dihedral_angle_d5.478303
ELECTRON MICROSCOPYf_chiral_restr0.04384
ELECTRON MICROSCOPYf_plane_restr0.005379

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