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- PDB-9c2f: Structure of Calcium-Sensing Receptor in complex with positive al... -

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Basic information

Entry
Database: PDB / ID: 9c2f
TitleStructure of Calcium-Sensing Receptor in complex with positive allosteric modulator '54149
Components(Extracellular calcium-sensing ...) x 2
KeywordsMEMBRANE PROTEIN / G-protein coupled receptor / calcium-sensing
Function / homology
Function and homology information


regulation of presynaptic membrane potential / bile acid secretion / chemosensory behavior / response to fibroblast growth factor / cellular response to peptide / cellular response to vitamin D / phosphatidylinositol-4,5-bisphosphate phospholipase C activity / Class C/3 (Metabotropic glutamate/pheromone receptors) / calcium ion import / positive regulation of positive chemotaxis ...regulation of presynaptic membrane potential / bile acid secretion / chemosensory behavior / response to fibroblast growth factor / cellular response to peptide / cellular response to vitamin D / phosphatidylinositol-4,5-bisphosphate phospholipase C activity / Class C/3 (Metabotropic glutamate/pheromone receptors) / calcium ion import / positive regulation of positive chemotaxis / fat pad development / cellular response to hepatocyte growth factor stimulus / amino acid binding / branching morphogenesis of an epithelial tube / positive regulation of calcium ion import / positive regulation of vasoconstriction / regulation of calcium ion transport / cellular response to low-density lipoprotein particle stimulus / anatomical structure morphogenesis / detection of calcium ion / JNK cascade / axon terminus / ossification / chloride transmembrane transport / response to ischemia / cellular response to glucose stimulus / G protein-coupled receptor activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / positive regulation of insulin secretion / vasodilation / integrin binding / intracellular calcium ion homeostasis / presynaptic membrane / G alpha (i) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / basolateral plasma membrane / G alpha (q) signalling events / cellular response to hypoxia / transmembrane transporter binding / positive regulation of ERK1 and ERK2 cascade / apical plasma membrane / G protein-coupled receptor signaling pathway / neuronal cell body / positive regulation of cell population proliferation / calcium ion binding / positive regulation of gene expression / protein kinase binding / glutamatergic synapse / cell surface / protein homodimerization activity / identical protein binding / plasma membrane
Similarity search - Function
GPCR, family 3, extracellular calcium-sensing receptor-related / G-protein coupled receptors family 3 signature 1. / G-protein coupled receptors family 3 signature 3. / G-protein coupled receptors family 3 signature 2. / GPCR, family 3, nine cysteines domain / GPCR, family 3, nine cysteines domain superfamily / Nine Cysteines Domain of family 3 GPCR / GPCR, family 3, conserved site / GPCR, family 3 / G-protein coupled receptors family 3 profile. ...GPCR, family 3, extracellular calcium-sensing receptor-related / G-protein coupled receptors family 3 signature 1. / G-protein coupled receptors family 3 signature 3. / G-protein coupled receptors family 3 signature 2. / GPCR, family 3, nine cysteines domain / GPCR, family 3, nine cysteines domain superfamily / Nine Cysteines Domain of family 3 GPCR / GPCR, family 3, conserved site / GPCR, family 3 / G-protein coupled receptors family 3 profile. / GPCR family 3, C-terminal / 7 transmembrane sweet-taste receptor of 3 GCPR / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I
Similarity search - Domain/homology
: / PHOSPHATE ION / TRYPTOPHAN / Extracellular calcium-sensing receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsWu, C. / Skiniotis, G.
Funding support United States, 2items
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
DepositionMay 30, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 2, 2024Provider: repository / Type: Initial release
Revision 1.0Oct 2, 2024Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Oct 2, 2024Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Oct 2, 2024Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Oct 2, 2024Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Oct 2, 2024Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.2May 28, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1May 28, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Extracellular calcium-sensing receptor
B: Extracellular calcium-sensing receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)217,06422
Polymers213,9622
Non-polymers3,10220
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Extracellular calcium-sensing ... , 2 types, 2 molecules AB

#1: Protein Extracellular calcium-sensing receptor / CaR / CaSR / hCasR / Parathyroid cell calcium-sensing receptor 1 / PCaR1


Mass: 108023.055 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CASR, GPRC2A, PCAR1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P41180
#2: Protein Extracellular calcium-sensing receptor / CaR / CaSR / hCasR / Parathyroid cell calcium-sensing receptor 1 / PCaR1


Mass: 105938.789 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CASR, GPRC2A, PCAR1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P41180

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Sugars , 2 types, 6 molecules

#3: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#4: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 4 types, 14 molecules

#5: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Ca
#6: Chemical ChemComp-TRP / TRYPTOPHAN


Type: L-peptide linking / Mass: 204.225 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C11H12N2O2
#7: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#8: Chemical ChemComp-A1ATX / (1R)-1-(2H-1,3-benzodioxol-4-yl)-N-[2-(1,2-benzothiazol-3-yl)ethyl]ethan-1-amine


Mass: 326.413 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H18N2O2S / Feature type: SUBJECT OF INVESTIGATION

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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

ComponentName: Calcium-sensing receptor bound to compound '54149 / Type: COMPLEX / Entity ID: #1-#2 / 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
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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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: 1500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 318351 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00312486
ELECTRON MICROSCOPYf_angle_d0.53216962
ELECTRON MICROSCOPYf_dihedral_angle_d6.0211793
ELECTRON MICROSCOPYf_chiral_restr0.0431928
ELECTRON MICROSCOPYf_plane_restr0.0042130

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