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- EMDB-34848: Structure of PKD2-F604P (Polycystin-2, TRPP2) with ML-SA1 -

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Basic information

Entry
Database: EMDB / ID: EMD-34848
TitleStructure of PKD2-F604P (Polycystin-2, TRPP2) with ML-SA1
Map data
Sample
  • Complex: Structure of PKD2-F604P (Polycystin-2, TRPP2) with ML-SA1
    • Protein or peptide: Polycystin-2Polycystin 2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CALCIUM IONCalcium
  • Ligand: 2-{2-oxo-2-[(4S)-2,2,4-trimethyl-3,4-dihydroquinolin-1(2H)-yl]ethyl}-1H-isoindole-1,3(2H)-dione
Keywordsmembrane protein
Function / homology
Function and homology information


detection of nodal flow / metanephric smooth muscle tissue development / metanephric cortex development / metanephric cortical collecting duct development / metanephric distal tubule development / polycystin complex / mesonephric tubule development / mesonephric duct development / : / metanephric part of ureteric bud development ...detection of nodal flow / metanephric smooth muscle tissue development / metanephric cortex development / metanephric cortical collecting duct development / metanephric distal tubule development / polycystin complex / mesonephric tubule development / mesonephric duct development / : / metanephric part of ureteric bud development / determination of liver left/right asymmetry / renal tubule morphogenesis / metanephric ascending thin limb development / HLH domain binding / basal cortex / metanephric mesenchyme development / metanephric S-shaped body morphogenesis / renal artery morphogenesis / positive regulation of inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity / migrasome / cilium organization / VxPx cargo-targeting to cilium / detection of mechanical stimulus / regulation of calcium ion import / cation channel complex / calcium-induced calcium release activity / muscle alpha-actinin binding / placenta blood vessel development / voltage-gated monoatomic ion channel activity / cellular response to hydrostatic pressure / outward rectifier potassium channel activity / voltage-gated monoatomic cation channel activity / non-motile cilium / cellular response to fluid shear stress / cellular response to osmotic stress / voltage-gated sodium channel activity / actinin binding / motile cilium / transcription regulator inhibitor activity / inorganic cation transmembrane transport / determination of left/right symmetry / aorta development / protein heterotetramerization / neural tube development / ciliary membrane / branching involved in ureteric bud morphogenesis / negative regulation of G1/S transition of mitotic cell cycle / spinal cord development / heart looping / cytoplasmic side of endoplasmic reticulum membrane / voltage-gated potassium channel activity / potassium channel activity / cell surface receptor signaling pathway via JAK-STAT / centrosome duplication / sodium ion transmembrane transport / negative regulation of ryanodine-sensitive calcium-release channel activity / voltage-gated calcium channel activity / embryonic placenta development / cellular response to cAMP / release of sequestered calcium ion into cytosol / monoatomic cation channel activity / potassium ion transmembrane transport / cellular response to calcium ion / cytoskeletal protein binding / basal plasma membrane / ciliary basal body / liver development / establishment of localization in cell / lumenal side of endoplasmic reticulum membrane / protein tetramerization / phosphoprotein binding / calcium ion transmembrane transport / cytoplasmic vesicle membrane / cilium / mitotic spindle / Wnt signaling pathway / intracellular calcium ion homeostasis / cellular response to reactive oxygen species / positive regulation of nitric oxide biosynthetic process / calcium ion transport / cell-cell junction / lamellipodium / regulation of cell population proliferation / heart development / ATPase binding / positive regulation of cytosolic calcium ion concentration / basolateral plasma membrane / protein homotetramerization / transmembrane transporter binding / regulation of cell cycle / negative regulation of cell population proliferation / signaling receptor binding / calcium ion binding / endoplasmic reticulum membrane / positive regulation of gene expression / Golgi apparatus / endoplasmic reticulum / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / extracellular exosome
Similarity search - Function
Ferredoxin I 4Fe-4S cluster domain / Polycystin domain / Polycystin domain / Polycystic kidney disease type 2 protein / Polycystin cation channel, PKD1/PKD2 / Polycystin cation channel / Voltage-dependent channel domain superfamily / EF-hand calcium-binding domain profile. / EF-hand domain / EF-hand domain pair
Similarity search - Domain/homology
Biological speciesHomo (humans) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsChen MY / Su Q / Wang ZF / Yu Y
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31930059 China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2024
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
DepositionNov 25, 2022-
Header (metadata) releaseMar 27, 2024-
Map releaseMar 27, 2024-
UpdateMar 27, 2024-
Current statusMar 27, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_34848.png

Downloads & links

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Map

FileDownload / File: emd_34848.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.087 Å
Density
Contour LevelBy AUTHOR: 0.0208
Minimum - Maximum-0.03470162 - 0.07193341
Average (Standard dev.)0.00046153014 (±0.0033544297)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 260.88 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_34848_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_34848_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Structure of PKD2-F604P (Polycystin-2, TRPP2) with ML-SA1

EntireName: Structure of PKD2-F604P (Polycystin-2, TRPP2) with ML-SA1
Components
  • Complex: Structure of PKD2-F604P (Polycystin-2, TRPP2) with ML-SA1
    • Protein or peptide: Polycystin-2Polycystin 2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CALCIUM IONCalcium
  • Ligand: 2-{2-oxo-2-[(4S)-2,2,4-trimethyl-3,4-dihydroquinolin-1(2H)-yl]ethyl}-1H-isoindole-1,3(2H)-dione

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Supramolecule #1: Structure of PKD2-F604P (Polycystin-2, TRPP2) with ML-SA1

SupramoleculeName: Structure of PKD2-F604P (Polycystin-2, TRPP2) with ML-SA1
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo (humans)

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Macromolecule #1: Polycystin-2

MacromoleculeName: Polycystin-2 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 66.029828 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: 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: Polycystin-2

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

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 2 / Number of copies: 12 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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Macromolecule #3: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 3 / Number of copies: 1 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Macromolecule #4: 2-{2-oxo-2-[(4S)-2,2,4-trimethyl-3,4-dihydroquinolin-1(2H)-yl]eth...

MacromoleculeName: 2-{2-oxo-2-[(4S)-2,2,4-trimethyl-3,4-dihydroquinolin-1(2H)-yl]ethyl}-1H-isoindole-1,3(2H)-dione
type: ligand / ID: 4 / Number of copies: 4 / Formula: AQV
Molecular weightTheoretical: 362.422 Da
Chemical component information

ChemComp-AQV:
2-{2-oxo-2-[(4S)-2,2,4-trimethyl-3,4-dihydroquinolin-1(2H)-yl]ethyl}-1H-isoindole-1,3(2H)-dione

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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

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.4000000000000001 µm
Image recordingFilm 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 modelType of model: NONE
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 163172

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