Structural basis of regulation of PKD2 by steroids
EMSL Project ID
50908
Abstract
Polycystic kidney disease 1 (PKD1) and PKD2 are fundamental for normal development and functioning of the renal and cardiovascular systems and, when rendered defective by genetic mutations, cause a prevalent life-threatening autosomal dominant polycystic kidney disease (ADPKD) in human. PKD1 is a putative 11-transmembrane spanning receptor with a remarkable large ligand recognition and/or adhesive N-terminal ectodomain (>3000 residues), wheras PKD2 is a Na+/K+-conducting ion channel of the transient receptor potential (TRP) superfamily. PKD1 and PKD2 can function independent of each other in some tissues, while they also co-assemble into a sensory receptor/ion channel apparatus at primary cilia where they are conceptually proposed to detect and respond to mechanical force of fluid shear and/or as-yet unidentified chemical stimuli. Nevertheless, how PKD1, PKD2, or the PKD1/2 complex is activated or regulated in vivo remains poorly understood. In order to fill this major knowledge gap, our collaborator, Markus Delling group, recently performed a small-scale screening campaign focusing on cilium-enriched molecules given the prominent roles of the PKD proteins in cilia signaling. Indeed, they identified a cilium-enriched steroid molecule that significantly increases open probability of the PKD2 channel. In this proposal, we seek to determine a high-resolution structure of PKD2 in complex with this steroid molecule to understand its mechanism of action. Successful completion of this proposal will not only reveal an important regulatory site for an endogenous small molecule in PKD2 for the first time; it will also help develop novel steroid-like molecules to therapeutically target this site for treating ADPKD patients.
Project Details
Start Date
2019-05-15
End Date
2020-01-31
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members