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- EMDB-45901: Focused refinement of the Heptahelical transmembrane (7TM) domain... -

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Entry
Database: EMDB / ID: EMD-45901
TitleFocused refinement of the Heptahelical transmembrane (7TM) domain of the calcium-sensing receptor bound to positive modulator '54149
Map data
Sample
  • Complex: Calcium-sensing receptor bound to compound '54149
KeywordsG-protein coupled receptor / calcium-sensing / membrane protein
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsWu C / Skiniotis G
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)RO1 NS122394 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)RO1 DK132902 United States
CitationJournal: Science / Year: 2024
Title: Large library docking identifies positive allosteric modulators of the calcium-sensing receptor.
Authors: Fangyu Liu / Cheng-Guo Wu / Chia-Ling Tu / Isabella Glenn / Justin Meyerowitz / Anat Levit Kaplan / Jiankun Lyu / Zhiqiang Cheng / Olga O Tarkhanova / Yurii S Moroz / John J Irwin / Wenhan ...Authors: Fangyu Liu / Cheng-Guo Wu / Chia-Ling Tu / Isabella Glenn / Justin Meyerowitz / Anat Levit Kaplan / Jiankun Lyu / Zhiqiang Cheng / Olga O Tarkhanova / Yurii S Moroz / John J Irwin / Wenhan Chang / Brian K Shoichet / Georgios Skiniotis /
Abstract: Positive allosteric modulator (PAM) drugs enhance the activation of the calcium-sensing receptor (CaSR) and suppress parathyroid hormone (PTH) secretion. Unfortunately, these hyperparathyroidism- ...Positive allosteric modulator (PAM) drugs enhance the activation of the calcium-sensing receptor (CaSR) and suppress parathyroid hormone (PTH) secretion. Unfortunately, these hyperparathyroidism-treating drugs can induce hypocalcemia and arrhythmias. Seeking improved modulators, we docked libraries of 2.7 million and 1.2 billion molecules against the CaSR structure. The billion-molecule docking found PAMs with a 2.7-fold higher hit rate than the million-molecule library, with hits up to 37-fold more potent. Structure-based optimization led to nanomolar leads. In ex vivo organ assays, one of these PAMs was 100-fold more potent than the standard of care, cinacalcet, and reduced serum PTH levels in mice without the hypocalcemia typical of CaSR drugs. As determined from cryo-electron microscopy structures, the PAMs identified here promote CaSR conformations that more closely resemble the activated state than those induced by the established drugs.
History
DepositionJul 24, 2024-
Header (metadata) releaseOct 2, 2024-
Map releaseOct 2, 2024-
UpdateOct 2, 2024-
Current statusOct 2, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_45901.png

Downloads & links

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Map

FileDownload / File: emd_45901.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.75 Å/pix.
x 512 pix.
= 384. Å		0.75 Å/pix.
x 512 pix.
= 384. Å		0.75 Å/pix.
x 512 pix.
= 384. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.75 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.56467205 - 0.87213665
Average (Standard dev.)-0.00021574956 (±0.010963157)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 384.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_45901_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_45901_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Calcium-sensing receptor bound to compound '54149

EntireName: Calcium-sensing receptor bound to compound '54149
Components
  • Complex: Calcium-sensing receptor bound to compound '54149

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Supramolecule #1: Calcium-sensing receptor bound to compound '54149

SupramoleculeName: Calcium-sensing receptor bound to compound '54149 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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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 / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7m3f

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 318351
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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