8hk7 | pdb_00008hk7
Structure of PKD2-F604P (Polycystin-2, TRPP2) with ML-SA1
Structural highlights
DiseasePKD2_HUMAN Defects in PKD2 are the cause of polycystic kidney disease 2 (PKD2) [MIM:613095. PKD2 is a disorder characterized by progressive formation and enlargement of cysts in both kidneys, typically leading to end-stage renal disease in adult life. Cysts also occurs in the liver and other organs. It represents approximately 15% of the cases of autosomal dominant polycystic kidney disease. PKD2 is clinically milder than PKD1 but it has a deleterious impact on overall life expectancy.[1] [2] [3] [4] [5] [6] [7] [8] [9] FunctionPKD2_HUMAN Involved in fluid-flow mechanosensation by the primary cilium in renal epithelium (By similarity). PKD1 and PKD2 may function through a common signaling pathway that is necessary for normal tubulogenesis (By similarity). Acts as a regulator of cilium length, together with PKD1 (By similarity). The dynamic control of cilium length is essential in the regulation of mechanotransductive signaling. The cilium length response creates a negative feedback loop whereby fluid shear-mediated deflection of the primary cilium, which decreases intracellular cAMP, leads to cilium shortening and thus decreases flow-induced signaling (By similarity). Functions as a calcium permeable cation channel. Publication Abstract from PubMedMutations in the PKD2 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. Molecular and structural basis of the dual regulation of the polycystin-2 ion channel by small-molecule ligands.,Wang Z, Chen M, Su Q, Morais TDC, Wang Y, Nazginov E, Pillai AR, Qian F, Shi Y, Yu Y Proc Natl Acad Sci U S A. 2024 Mar 19;121(12):e2316230121. doi: , 10.1073/pnas.2316230121. Epub 2024 Mar 14. PMID:38483987[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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