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- PDB-7zly: Crystal structure of human GPCR Niacin receptor (HCA2) expressed ... -

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Basic information

Entry
Database: PDB / ID: 7zly
TitleCrystal structure of human GPCR Niacin receptor (HCA2) expressed from Spodoptera frugiperda
ComponentsHydroxycarboxylic acid receptor 2,Soluble cytochrome b562
KeywordsMEMBRANE PROTEIN / Niacin receptor / hydroxycarboxylic acid receptor 2 / HCA2 / GPCR / membrane protein structure
Function / homology
Function and homology information


nicotinic acid receptor activity / Hydroxycarboxylic acid-binding receptors / neutrophil apoptotic process / Class A/1 (Rhodopsin-like receptors) / positive regulation of neutrophil apoptotic process / positive regulation of adiponectin secretion / negative regulation of lipid catabolic process / cell junction / G alpha (i) signalling events / electron transfer activity ...nicotinic acid receptor activity / Hydroxycarboxylic acid-binding receptors / neutrophil apoptotic process / Class A/1 (Rhodopsin-like receptors) / positive regulation of neutrophil apoptotic process / positive regulation of adiponectin secretion / negative regulation of lipid catabolic process / cell junction / G alpha (i) signalling events / electron transfer activity / periplasmic space / iron ion binding / G protein-coupled receptor signaling pathway / heme binding / plasma membrane
Similarity search - Function
Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / 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
OLEIC ACID / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / Soluble cytochrome b562 / Hydroxycarboxylic acid receptor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Escherichia coli (E. coli)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsYang, Y. / Kang, H.J. / Gao, R.G. / Wang, J.J. / FiBerto, J.F. / Wu, L.J. / Tong, J.H. / Han, G.W. / Qu, L. / Wu, Y.R. ...Yang, Y. / Kang, H.J. / Gao, R.G. / Wang, J.J. / FiBerto, J.F. / Wu, L.J. / Tong, J.H. / Han, G.W. / Qu, L. / Wu, Y.R. / Pileski, R. / Li, X.M. / Zhang, X.C. / Zhao, S.W. / Kenakin, T. / Wang, Q. / Stevens, R.C. / Peng, W. / Roth, B.L. / Rao, Z.H. / Liu, Z.J.
Funding support China, 5items
OrganizationGrant numberCountry
National Basic Research Program of China (973 Program)Grant No. 2017YFC0840300 China
Chinese Academy of SciencesGrant No. XDB08020200 China
National Science Foundation (NSF, China)31330019 China
Ministry of Science and Technology (MoST, China)2014CB910400 and 2015CB910104 China
National Natural Science Foundation of China (NSFC)2016YCF0905902 China
CitationJournal: Nat Commun / Year: 2023
Title: Structural insights into the human niacin receptor HCA2-G signalling complex.
Authors: Yang Yang / Hye Jin Kang / Ruogu Gao / Jingjing Wang / Gye Won Han / Jeffrey F DiBerto / Lijie Wu / Jiahui Tong / Lu Qu / Yiran Wu / Ryan Pileski / Xuemei Li / Xuejun Cai Zhang / Suwen Zhao ...Authors: Yang Yang / Hye Jin Kang / Ruogu Gao / Jingjing Wang / Gye Won Han / Jeffrey F DiBerto / Lijie Wu / Jiahui Tong / Lu Qu / Yiran Wu / Ryan Pileski / Xuemei Li / Xuejun Cai Zhang / Suwen Zhao / Terry Kenakin / Quan Wang / Raymond C Stevens / Wei Peng / Bryan L Roth / Zihe Rao / Zhi-Jie Liu /
Abstract: The hydroxycarboxylic acid receptor 2 (HCA2) agonist niacin has been used as treatment for dyslipidemia for several decades albeit with skin flushing as a common side-effect in treated individuals. ...The hydroxycarboxylic acid receptor 2 (HCA2) agonist niacin has been used as treatment for dyslipidemia for several decades albeit with skin flushing as a common side-effect in treated individuals. Extensive efforts have been made to identify HCA2 targeting lipid lowering agents with fewer adverse effects, despite little being known about the molecular basis of HCA2 mediated signalling. Here, we report the cryo-electron microscopy structure of the HCA2-G signalling complex with the potent agonist MK-6892, along with crystal structures of HCA2 in inactive state. These structures, together with comprehensive pharmacological analysis, reveal the ligand binding mode and activation and signalling mechanisms of HCA2. This study elucidates the structural determinants essential for HCA2 mediated signalling and provides insights into ligand discovery for HCA2 and related receptors.
History
DepositionApr 17, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 12, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

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Assembly

Deposited unit
A: Hydroxycarboxylic acid receptor 2,Soluble cytochrome b562
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,8698
Polymers49,8181
Non-polymers2,0517
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2450 Å2
ΔGint15 kcal/mol
Surface area19870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.080, 82.150, 86.310
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21221

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Components

#1: Protein Hydroxycarboxylic acid receptor 2,Soluble cytochrome b562 / G-protein coupled receptor 109A / G-protein coupled receptor HM74A / Niacin receptor 1 / Nicotinic ...G-protein coupled receptor 109A / G-protein coupled receptor HM74A / Niacin receptor 1 / Nicotinic acid receptor / Cytochrome b-562


Mass: 49817.527 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Escherichia coli (E. coli)
Gene: HCAR2, GPR109A, HCA2, HM74A, NIACR1, cybC / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8TDS4, UniProt: P0ABE7
#2: Chemical
ChemComp-OLA / OLEIC ACID / Oleic acid


Mass: 282.461 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C18H34O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-OLC / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / 1-Oleoyl-R-glycerol


Mass: 356.540 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H40O4 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.88 Å3/Da / Density % sol: 57.37 %
Crystal growTemperature: 293 K / Method: lipidic cubic phase
Details: 100mM pH5.4 sodium citrate, 60mM ammonium citrate, 36% PEG400, and 3% Additive 80 (40% PPG)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL41XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Nov 27, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→47.972 Å / Num. obs: 25559 / % possible obs: 95.76 % / Redundancy: 5.6 % / CC1/2: 0.99 / Net I/σ(I): 10.18
Reflection shellResolution: 2.7→2.752 Å / Num. unique obs: 1101 / CC1/2: 0.69

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Processing

Software
NameClassification
BUSTERrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4PXZ

4pxz


Resolution: 2.7→47.97 Å / Cross valid method: THROUGHOUT
RfactorNum. reflection% reflection
Rfree0.28 --
Rwork0.25 --
obs-25559 95.76 %
Displacement parametersBiso max: 193.39 Å2 / Biso min: 37.94 Å2
Refinement stepCycle: LAST / Resolution: 2.7→47.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3088 0 94 0 3182

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