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Open data
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Basic information
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Title | Structure of PKD2-F604P complex | |||||||||
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Function / homology | ![]() detection of nodal flow / metanephric smooth muscle tissue development / metanephric cortex development / metanephric cortical collecting duct development / metanephric distal tubule development / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | |||||||||
Biological species | ![]() ![]() | |||||||||
Method | ![]() | |||||||||
![]() | Chen MY / Su Q / Wang ZF / Yu Y | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Molecular and structural basis of the dual regulation of the polycystin-2 ion channel by small-molecule ligands. Authors: Zhifei Wang / Mengying Chen / Qiang Su / Tiago D C Morais / Yan Wang / Elianna Nazginov / Akhilraj R Pillai / Feng Qian / Yigong Shi / Yong Yu / ![]() ![]() Abstract: Mutations in the gene, which encodes the polycystin-2 (PC2, also called TRPP2) protein, lead to autosomal dominant polycystic kidney disease (ADPKD). As a member of the transient receptor potential ...Mutations in the gene, which encodes the polycystin-2 (PC2, also called TRPP2) protein, lead to autosomal dominant polycystic kidney disease (ADPKD). As a member of the transient receptor potential (TRP) channel superfamily, PC2 functions as a non-selective cation channel. The activation and regulation of the PC2 channel are largely unknown, and direct binding of small-molecule ligands to this channel has not been reported. In this work, we found that most known small-molecule agonists of the mucolipin TRP (TRPML) channels inhibit the activity of the PC2_F604P, a gain-of-function mutant of the PC2 channel. However, two of them, ML-SA1 and SF-51, have dual regulatory effects, with low concentration further activating PC2_F604P, and high concentration leading to inactivation of the channel. With two cryo-electron microscopy (cryo-EM) structures, a molecular docking model, and mutagenesis results, we identified two distinct binding sites of ML-SA1 in PC2_F604P that are responsible for activation and inactivation, respectively. These results provide structural and functional insights into how ligands regulate PC2 channel function through unusual mechanisms and may help design compounds that are more efficient and specific in regulating the PC2 channel and potentially also for ADPKD treatment. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 49.3 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 14.7 KB 14.7 KB | Display Display | ![]() |
Images | ![]() | 132.3 KB | ||
Filedesc metadata | ![]() | 5.6 KB | ||
Others | ![]() ![]() | 37.1 MB 37.1 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8k3sMC ![]() 8hk7C M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 1.087 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_36858_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_36858_half_map_2.map | ||||||||||||
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Density Histograms |
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Sample components
-Entire : polycystin-2
Entire | Name: polycystin-2![]() |
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Components |
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-Supramolecule #1: polycystin-2
Supramolecule | Name: polycystin-2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() ![]() |
-Macromolecule #1: Polycystin-2
Macromolecule | Name: Polycystin-2 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 66.029828 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MSAWSHPQFE KGGGSGGGSG GSAWSHPQFE KGSAAAPRVA WAERLVRGLR GLWGTRLMEE SSTNREKYLK SVLRELVTYL LFLIVLCIL TYGMMSSNVY YYTRMMSQLF LDTPVSKTEK TNFKTLSSME DFWKFTEGSL LDGLYWKMQP SNQTEADNRS F IFYENLLL ...String: MSAWSHPQFE KGGGSGGGSG GSAWSHPQFE KGSAAAPRVA WAERLVRGLR GLWGTRLMEE SSTNREKYLK SVLRELVTYL LFLIVLCIL TYGMMSSNVY YYTRMMSQLF LDTPVSKTEK TNFKTLSSME DFWKFTEGSL LDGLYWKMQP SNQTEADNRS F IFYENLLL GVPRIRQLRV RNGSCSIPQD LRDEIKECYD VYSVSSEDRA PFGPRNGTAW IYTSEKDLNG SSHWGIIATY SG AGYYLDL SRTREETAAQ VASLKKNVWL DRGTRATFID FSVYNANINL FCVVRLLVEF PATGGVIPSW QFQPLKLIRY VTT FDFFLA ACEIIFCFFI FYYVVEEILE IRIHKLHYFR SFWNCLDVVI VVLSVVAIGI NIYRTSNVEV LLQFLEDQNT FPNF EHLAY WQIQFNNIAA VTVFFVWIKL FKFINFNRTM SQLSTTMSRC AKDLFGFAIM PFIIFLAYAQ LAYLVFGTQV DDFST FQEC IFTQFRIILG DINFAEIEEA NRVLGPIYFT TFVFFMFFIL LNMFLAIIND TYSEVKSDLA QQKAEMELSD LIRKGY HKA LVKLKLKK UniProtKB: ![]() |
-Macromolecule #2: DI-PALMITOYL-3-SN-PHOSPHATIDYLETHANOLAMINE
Macromolecule | Name: DI-PALMITOYL-3-SN-PHOSPHATIDYLETHANOLAMINE / type: ligand / ID: 2 / Number of copies: 4 / Formula: PEF |
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Molecular weight | Theoretical: 691.959 Da |
Chemical component information | ![]() ChemComp-PEF: |
-Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 12 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ![]() ChemComp-NAG: |
-Macromolecule #4: CALCIUM ION
Macromolecule | Name: CALCIUM ION / type: ligand / ID: 4 / Number of copies: 1 / Formula: CA |
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Molecular weight | Theoretical: 40.078 Da |
-Experimental details
-Structure determination
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Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.4 |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD![]() |
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2 |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Startup model | Type of model: PDB ENTRY PDB model - PDB ID: |
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Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 413044 |