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Yorodumi- PDB-9c1p: Structure of Calcium-Sensing Receptor in complex with positive al... -
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-Basic information
Entry | Database: PDB / ID: 9c1p | |||||||||
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Title | Structure of Calcium-Sensing Receptor in complex with positive allosteric modulator '6218 | |||||||||
Components | (Extracellular calcium-sensing ...) x 2 | |||||||||
Keywords | MEMBRANE PROTEIN / G-protein coupled receptor / calcium-sensing | |||||||||
Function / homology | Function and homology information bile acid secretion / chemosensory behavior / response to fibroblast growth factor / cellular response to peptide / cellular response to vitamin D / phosphatidylinositol phospholipase C activity / Class C/3 (Metabotropic glutamate/pheromone receptors) / calcium ion import / positive regulation of positive chemotaxis / fat pad development ...bile acid secretion / chemosensory behavior / response to fibroblast growth factor / cellular response to peptide / cellular response to vitamin D / phosphatidylinositol phospholipase C activity / Class C/3 (Metabotropic glutamate/pheromone receptors) / calcium ion import / positive regulation of positive chemotaxis / fat pad development / amino acid binding / cellular response to hepatocyte growth factor stimulus / branching morphogenesis of an epithelial tube / positive regulation of calcium ion import / regulation of calcium ion transport / cellular response to low-density lipoprotein particle stimulus / detection of calcium ion / anatomical structure morphogenesis / positive regulation of vasoconstriction / axon terminus / JNK cascade / chloride transmembrane transport / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / ossification / response to ischemia / G protein-coupled receptor activity / cellular response to glucose stimulus / positive regulation of insulin secretion / intracellular calcium ion homeostasis / vasodilation / integrin binding / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / cellular response to hypoxia / basolateral plasma membrane / G alpha (q) signalling events / transmembrane transporter binding / positive regulation of ERK1 and ERK2 cascade / G protein-coupled receptor signaling pathway / apical plasma membrane / neuronal cell body / calcium ion binding / positive regulation of cell population proliferation / positive regulation of gene expression / protein kinase binding / cell surface / protein homodimerization activity / identical protein binding / plasma membrane Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å | |||||||||
Authors | Wu, C. / Skiniotis, G. | |||||||||
Funding support | United States, 2items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 9c1p.cif.gz | 295.2 KB | Display | PDBx/mmCIF format |
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PDB format | pdb9c1p.ent.gz | Display | PDB format | |
PDBx/mmJSON format | 9c1p.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 9c1p_validation.pdf.gz | 1.3 MB | Display | wwPDB validaton report |
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Full document | 9c1p_full_validation.pdf.gz | 1.3 MB | Display | |
Data in XML | 9c1p_validation.xml.gz | 45.8 KB | Display | |
Data in CIF | 9c1p_validation.cif.gz | 68.5 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/c1/9c1p ftp://data.pdbj.org/pub/pdb/validation_reports/c1/9c1p | HTTPS FTP |
-Related structure data
Related structure data | 45127MC 9c2fC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Extracellular calcium-sensing ... , 2 types, 2 molecules AB
#1: Protein | 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 |
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#2: Protein | 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 |
-Sugars , 1 types, 6 molecules
#3: Sugar | ChemComp-NAG / |
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-Non-polymers , 4 types, 14 molecules
#4: Chemical | ChemComp-CA / #5: Chemical | #6: Chemical | #7: Chemical | Mass: 337.482 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H23N3S / Feature type: SUBJECT OF INVESTIGATION |
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-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Calcium-sensing receptor bound to compound '6218 / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Spodoptera frugiperda (fall armyworm) |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: TFS KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 500 nm |
Image recording | Electron dose: 55 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
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3D reconstruction | Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 346741 / Symmetry type: POINT | ||||||||||||||||||||||||
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