Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Molecular and structural basis of the dual regulation of the polycystin-2 ion channel by small-molecule ligands.
Journal, issue, pages	Proc Natl Acad Sci U S A, Vol. 121, Issue 12, Page e2316230121, Year 2024
Publish date	Mar 19, 2024
Authors	Zhifei Wang / Mengying Chen / Qiang Su / Tiago D C Morais / Yan Wang / Elianna Nazginov / Akhilraj R Pillai / Feng Qian / Yigong Shi / Yong Yu /
PubMed 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.
External links	Proc Natl Acad Sci U S A / PubMed:38483987 / PubMed Central
Methods	EM (single particle)
Resolution	3.0 Å
Structure data	34848 8hk7 EMDB-34848, PDB-8hk7: Structure of PKD2-F604P (Polycystin-2, TRPP2) with ML-SA1 Method: EM (single particle) / Resolution: 3.0 Å
Chemicals	ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine ChemComp-CA: Unknown entry ChemComp-AQV: 2-{2-oxo-2-[(4S)-2,2,4-trimethyl-3,4-dihydroquinolin-1(2H)-yl]ethyl}-1H-isoindole-1,3(2H)-dione
Source	Homo (humans) homo sapiens (human)
Keywords	MEMBRANE PROTEIN