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- EMDB-45156: Structure of Calcium-Sensing Receptor in complex with positive al... -

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Basic information

Entry
Database: EMDB / ID: EMD-45156
TitleStructure of Calcium-Sensing Receptor in complex with positive allosteric modulator '54149
Map data
Sample
  • Complex: Calcium-sensing receptor bound to compound '54149
    • Protein or peptide: Extracellular calcium-sensing receptor
    • Protein or peptide: Extracellular calcium-sensing receptor
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CALCIUM ION
  • Ligand: TRYPTOPHAN
  • Ligand: PHOSPHATE ION
  • Ligand: (1R)-1-(2H-1,3-benzodioxol-4-yl)-N-[2-(1,2-benzothiazol-3-yl)ethyl]ethan-1-amine
KeywordsG-protein coupled receptor / calcium-sensing / membrane protein
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 / cellular response to hepatocyte growth factor stimulus / amino acid binding / 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 / axon terminus / positive regulation of vasoconstriction / 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 / cellular response to hypoxia / G alpha (i) signalling events / 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 / positive regulation of cell population proliferation / calcium ion binding / positive regulation of gene expression / protein kinase binding / 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 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 / G-protein coupled receptors family 3 signature 3. / 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 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 / G-protein coupled receptors family 3 signature 3. / 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
Extracellular calcium-sensing receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.8 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
DepositionMay 30, 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_45156.png

Downloads & links

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Map

FileDownload / File: emd_45156.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.75 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

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.75 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.24
Minimum - Maximum-0.33617365 - 1.3954186
Average (Standard dev.)0.008334695 (±0.025379354)
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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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
    • Protein or peptide: Extracellular calcium-sensing receptor
    • Protein or peptide: Extracellular calcium-sensing receptor
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CALCIUM ION
  • Ligand: TRYPTOPHAN
  • Ligand: PHOSPHATE ION
  • Ligand: (1R)-1-(2H-1,3-benzodioxol-4-yl)-N-[2-(1,2-benzothiazol-3-yl)ethyl]ethan-1-amine

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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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Macromolecule #1: Extracellular calcium-sensing receptor

MacromoleculeName: Extracellular calcium-sensing receptor / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 108.023055 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: WSHPQFEKGG GSGGGSGGSA WSHPQFEKGS AAAYGPDQRA QKKGDIILGG LFPIHFGVAA KDQDLKSRPE SVECIRYNFR GFRWLQAMI FAIEEINSSP ALLPNLTLGY RIFDTCNTVS KALEATLSFV AQNKIDSLNL DEFCNCSEHI PSTIAVVGAT G SGVSTAVA ...String:
WSHPQFEKGG GSGGGSGGSA WSHPQFEKGS AAAYGPDQRA QKKGDIILGG LFPIHFGVAA KDQDLKSRPE SVECIRYNFR GFRWLQAMI FAIEEINSSP ALLPNLTLGY RIFDTCNTVS KALEATLSFV AQNKIDSLNL DEFCNCSEHI PSTIAVVGAT G SGVSTAVA NLLGLFYIPQ VSYASSSRLL SNKNQFKSFL RTIPNDEHQA TAMADIIEYF RWNWVGTIAA DDDYGRPGIE KF REEAEER DICIDFSELI SQYSDEEEIQ HVVEVIQNST AKVIVVFSSG PDLEPLIKEI VRRNITGKIW LASEAWASSS LIA MPQYFH VVGGTIGFAL KAGQIPGFRE FLKKVHPRKS VHNGFAKEFW EETFNCHLQE GAKGPLPVDT FLRGHEESGD RFSN SSTAF RPLCTGDENI SSVETPYIDY THLRISYNVY LAVYSIAHAL QDIYTCLPGR GLFTNGSCAD IKKVEAWQVL KHLRH LNFT NNMGEQVTFD ECGDLVGNYS IINWHLSPED GSIVFKEVGY YNVYAKKGER LFINEEKILW SGFSREVPFS NCSRDC LAG TRKGIIEGEP TCCFECVECP DGEYSDETDA SACNKCPDDF WSNENHTSCI AKEIEFLSWT EPFGIALTLF AVLGIFL TA FVLGVFIKFR NTPIVKATNR ELSYLLLFSL LCCFSSSLFF IGEPQDWTCR LRQPAFGISF VLCISCILVK TNRVLLVF E AKIPTSFHRK WWGLNLQFLL VFLCTFMQIV ICVIWLYTAP PSSYRNQELE DEIIFITCHE GSLMALGFLI GYTCLLAAI CFFFAFKSRK LPENFNEAKF ITFSMLIFFI VWISFIPAYA STYGKFVSAV EVIAILAASF GLLACIFFNK IYIILFKPSR NTIEEVRCS TAAHAFKVAA RATLRRSNVT GSSTNNNEEE KSRLLEKENR ELEKIIAEKE ERVSELRHQL QSRQQLKKTN

UniProtKB: Extracellular calcium-sensing receptor

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Macromolecule #2: Extracellular calcium-sensing receptor

MacromoleculeName: Extracellular calcium-sensing receptor / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 105.938789 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DYKDDDDKAA AYGPDQRAQK KGDIILGGLF PIHFGVAAKD QDLKSRPESV ECIRYNFRGF RWLQAMIFAI EEINSSPALL PNLTLGYRI FDTCNTVSKA LEATLSFVAQ NKIDSLNLDE FCNCSEHIPS TIAVVGATGS GVSTAVANLL GLFYIPQVSY A SSSRLLSN ...String:
DYKDDDDKAA AYGPDQRAQK KGDIILGGLF PIHFGVAAKD QDLKSRPESV ECIRYNFRGF RWLQAMIFAI EEINSSPALL PNLTLGYRI FDTCNTVSKA LEATLSFVAQ NKIDSLNLDE FCNCSEHIPS TIAVVGATGS GVSTAVANLL GLFYIPQVSY A SSSRLLSN KNQFKSFLRT IPNDEHQATA MADIIEYFRW NWVGTIAADD DYGRPGIEKF REEAEERDIC IDFSELISQY SD EEEIQHV VEVIQNSTAK VIVVFSSGPD LEPLIKEIVR RNITGKIWLA SEAWASSSLI AMPQYFHVVG GTIGFALKAG QIP GFREFL KKVHPRKSVH NGFAKEFWEE TFNCHLQEGA KGPLPVDTFL RGHEESGDRF SNSSTAFRPL CTGDENISSV ETPY IDYTH LRISYNVYLA VYSIAHALQD IYTCLPGRGL FTNGSCADIK KVEAWQVLKH LRHLNFTNNM GEQVTFDECG DLVGN YSII NWHLSPEDGS IVFKEVGYYN VYAKKGERLF INEEKILWSG FSREVPFSNC SRDCLAGTRK GIIEGEPTCC FECVEC PDG EYSDETDASA CNKCPDDFWS NENHTSCIAK EIEFLSWTEP FGIALTLFAV LGIFLTAFVL GVFIKFRNTP IVKATNR EL SYLLLFSLLC CFSSSLFFIG EPQDWTCRLR QPAFGISFVL CISCILVKTN RVLLVFEAKI PTSFHRKWWG LNLQFLLV F LCTFMQIVIC VIWLYTAPPS SYRNQELEDE IIFITCHEGS LMALGFLIGY TCLLAAICFF FAFKSRKLPE NFNEAKFIT FSMLIFFIVW ISFIPAYAST YGKFVSAVEV IAILAASFGL LACIFFNKIY IILFKPSRNT IEEVRCSTAA HAFKVAARAT LRRSNVTST SVTSVNQAST SRLEGLQSEN HRLRMKITEL DKDLEEVTMQ LQDTPEKKTN

UniProtKB: Extracellular calcium-sensing receptor

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 5 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #5: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 5 / Number of copies: 8 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Macromolecule #6: TRYPTOPHAN

MacromoleculeName: TRYPTOPHAN / type: ligand / ID: 6 / Number of copies: 2 / Formula: TRP
Molecular weightTheoretical: 204.225 Da
Chemical component information

ChemComp-TRP:
TRYPTOPHAN

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Macromolecule #7: PHOSPHATE ION

MacromoleculeName: PHOSPHATE ION / type: ligand / ID: 7 / Number of copies: 2 / Formula: PO4
Molecular weightTheoretical: 94.971 Da
Chemical component information

ChemComp-PO4:
PHOSPHATE ION

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Macromolecule #8: (1R)-1-(2H-1,3-benzodioxol-4-yl)-N-[2-(1,2-benzothiazol-3-yl)ethy...

MacromoleculeName: (1R)-1-(2H-1,3-benzodioxol-4-yl)-N-[2-(1,2-benzothiazol-3-yl)ethyl]ethan-1-amine
type: ligand / ID: 8 / Number of copies: 2 / Formula: A1ATX
Molecular weightTheoretical: 326.413 Da

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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: 2.8 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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