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- PDB-8hk7: Structure of PKD2-F604P (Polycystin-2, TRPP2) with ML-SA1 -

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Basic information

Entry
Database: PDB / ID: 8hk7
TitleStructure of PKD2-F604P (Polycystin-2, TRPP2) with ML-SA1
ComponentsPolycystin-2
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 / renal tubule morphogenesis ...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 / renal tubule morphogenesis / determination of liver left/right asymmetry / metanephric ascending thin limb development / metanephric mesenchyme development / metanephric S-shaped body morphogenesis / basal cortex / placenta blood vessel development / renal artery morphogenesis / HLH domain binding / VxPx cargo-targeting to cilium / cilium organization / migrasome / cellular response to fluid shear stress / muscle alpha-actinin binding / regulation of calcium ion import / calcium-induced calcium release activity / detection of mechanical stimulus / determination of left/right symmetry / voltage-gated monoatomic ion channel activity / cellular response to hydrostatic pressure / aorta development / cation channel complex / branching involved in ureteric bud morphogenesis / neural tube development / non-motile cilium / outward rectifier potassium channel activity / motile cilium / actinin binding / cellular response to osmotic stress / voltage-gated sodium channel activity / negative regulation of G1/S transition of mitotic cell cycle / ciliary membrane / voltage-gated monoatomic cation channel activity / heart looping / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / protein heterotetramerization / spinal cord development / embryonic placenta development / cytoplasmic side of endoplasmic reticulum membrane / centrosome duplication / voltage-gated potassium channel activity / potassium channel activity / transcription regulator inhibitor activity / voltage-gated calcium channel activity / cell surface receptor signaling pathway via JAK-STAT / release of sequestered calcium ion into cytosol / monoatomic cation channel activity / cytoskeletal protein binding / potassium ion transmembrane transport / liver development / cellular response to calcium ion / cytoplasmic vesicle membrane / cellular response to cAMP / basal plasma membrane / sodium ion transmembrane transport / lumenal side of endoplasmic reticulum membrane / cellular response to reactive oxygen species / protein tetramerization / phosphoprotein binding / Wnt signaling pathway / mitotic spindle / calcium ion transmembrane transport / positive regulation of nitric oxide biosynthetic process / calcium ion transport / transmembrane transport / heart development / cell-cell junction / regulation of cell population proliferation / lamellipodium / ATPase binding / cilium / protein homotetramerization / ciliary basal body / basolateral plasma membrane / transmembrane transporter binding / regulation of cell cycle / cell surface receptor signaling pathway / negative regulation of cell population proliferation / signaling receptor binding / positive regulation of gene expression / calcium ion binding / endoplasmic reticulum membrane / Golgi apparatus / endoplasmic reticulum / positive regulation of transcription by RNA polymerase II / protein homodimerization activity / extracellular exosome / membrane / identical protein binding / plasma membrane / cytoplasm
Similarity search - Function
Ferredoxin I 4Fe-4S cluster domain / : / Polycystic kidney disease type 2 protein / Polycystin domain / Polycystin domain / 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
Chem-AQV / Polycystin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsChen, M.Y. / Su, Q. / Wang, Z.F. / Yu, Y.
Funding support China, 1items
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, 2022Deposition site: PDBJ / Processing site: RCSB
Revision 1.0Mar 27, 2024Provider: repository / Type: Initial release
Revision 1.0Mar 27, 2024Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Mar 27, 2024Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Mar 27, 2024Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
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Revision 1.0Mar 27, 2024Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Mar 27, 2024Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 27, 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 21, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1May 21, 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: Polycystin-2
B: Polycystin-2
C: Polycystin-2
D: Polycystin-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)268,26421
Polymers264,1194
Non-polymers4,14417
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Polycystin-2 / PC2 / Autosomal dominant polycystic kidney disease type II protein / Polycystic kidney disease 2 ...PC2 / Autosomal dominant polycystic kidney disease type II protein / Polycystic kidney disease 2 protein / Polycystwin / R48321 / Transient receptor potential cation channel subfamily P member 2


Mass: 66029.828 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PKD2, TRPP2 / Production host: Homo sapiens (human) / References: UniProt: Q13563
#2: 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.: 12 / 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
#3: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-AQV / 2-{2-oxo-2-[(4S)-2,2,4-trimethyl-3,4-dihydroquinolin-1(2H)-yl]ethyl}-1H-isoindole-1,3(2H)-dione


Mass: 362.422 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C22H22N2O3 / Feature type: SUBJECT OF INVESTIGATION
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: Structure of PKD2-F604P (Polycystin-2, TRPP2) with ML-SA1
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo (humans)
Source (recombinant)Organism: Homo (humans)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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: 2000 nm / Nominal defocus min: 1400 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: NONE
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 163172 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00715316
ELECTRON MICROSCOPYf_angle_d0.64720836
ELECTRON MICROSCOPYf_dihedral_angle_d26.9452056
ELECTRON MICROSCOPYf_chiral_restr0.0432380
ELECTRON MICROSCOPYf_plane_restr0.0042588

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