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- EMDB-36508: Cryo-EM map of human receptor R2 in complex with Gi protein -

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Basic information

Entry
Database: EMDB / ID: EMD-36508
TitleCryo-EM map of human receptor R2 in complex with Gi protein
Map data
Sample
  • Complex: HCA2 in complex with Gi heterotrimer
    • Complex: Nicotinic acid receptor in complex with Gi heterotrimer
    • Complex: scFv16
KeywordsComplex / Agonist / MEMBRANE PROTEIN
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.98 Å
AuthorsZhao C / Tian XW / Liu Y / Cheng L / Yan W / Shao ZH
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Mol Cell / Year: 2023
Title: Biased allosteric activation of ketone body receptor HCAR2 suppresses inflammation.
Authors: Chang Zhao / Heli Wang / Ying Liu / Lin Cheng / Bo Wang / Xiaowen Tian / Hong Fu / Chao Wu / Ziyan Li / Chenglong Shen / Jingjing Yu / Shengyong Yang / Hongbo Hu / Ping Fu / Liang Ma / ...Authors: Chang Zhao / Heli Wang / Ying Liu / Lin Cheng / Bo Wang / Xiaowen Tian / Hong Fu / Chao Wu / Ziyan Li / Chenglong Shen / Jingjing Yu / Shengyong Yang / Hongbo Hu / Ping Fu / Liang Ma / Chuanxin Wang / Wei Yan / Zhenhua Shao /
Abstract: Hydroxycarboxylic acid receptor 2 (HCAR2), modulated by endogenous ketone body β-hydroxybutyrate and exogenous niacin, is a promising therapeutic target for inflammation-related diseases. HCAR2 ...Hydroxycarboxylic acid receptor 2 (HCAR2), modulated by endogenous ketone body β-hydroxybutyrate and exogenous niacin, is a promising therapeutic target for inflammation-related diseases. HCAR2 mediates distinct pathophysiological events by activating G protein or β-arrestin effectors. Here, we characterize compound 9n as a G-biased allosteric modulator (BAM) of HCAR2 and exhibit anti-inflammatory efficacy in RAW264.7 macrophages via a specific HCAR2-G pathway. Furthermore, four structures of HCAR2-G complex bound to orthosteric agonists (niacin or monomethyl fumarate), compound 9n, and niacin together with compound 9n simultaneously reveal a common orthosteric site and a unique allosteric site. Combined with functional studies, we decipher the action framework of biased allosteric modulation of compound 9n on the orthosteric site. Moreover, co-administration of compound 9n with orthosteric agonists could enhance anti-inflammatory effects in the mouse model of colitis. Together, our study provides insight to understand the molecular pharmacology of the BAM and facilitates exploring the therapeutic potential of the BAM with orthosteric drugs.
History
DepositionJun 13, 2023-
Header (metadata) releaseSep 6, 2023-
Map releaseSep 6, 2023-
UpdateOct 11, 2023-
Current statusOct 11, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_36508.png

Downloads & links

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Map

FileDownload / File: emd_36508.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 256 pix.
= 217.6 Å		0.85 Å/pix.
x 256 pix.
= 217.6 Å		0.85 Å/pix.
x 256 pix.
= 217.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.368
Minimum - Maximum-2.8376143 - 4.252859
Average (Standard dev.)-0.0027813402 (±0.106031775)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 217.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_36508_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_36508_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : HCA2 in complex with Gi heterotrimer

EntireName: HCA2 in complex with Gi heterotrimer
Components
  • Complex: HCA2 in complex with Gi heterotrimer
    • Complex: Nicotinic acid receptor in complex with Gi heterotrimer
    • Complex: scFv16

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Supramolecule #1: HCA2 in complex with Gi heterotrimer

SupramoleculeName: HCA2 in complex with Gi heterotrimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5

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Supramolecule #2: Nicotinic acid receptor in complex with Gi heterotrimer

SupramoleculeName: Nicotinic acid receptor in complex with Gi heterotrimer
type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#3, #5
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: scFv16

SupramoleculeName: scFv16 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #4
Source (natural)Organism: Mus musculus (house mouse)

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Average electron dose: 62.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 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: 2.98 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 105460
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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