Inactivation-mimicking block of the epithelial calcium channel TRPV6

Bhardwaj, Rajesh; Lindinger, Sonja; Neuberger, Arthur; Nadezhdin, Kirill D.; Singh, Appu K.; R. Cunha, Micael; Derler, Isabella; Gyimesi, Gergely; Reymond, Jean-Louis; Hediger, Matthias A.; Romanin, Christoph; Sobolevsky, Alexander I. (2020). Inactivation-mimicking block of the epithelial calcium channel TRPV6. Science Advances, 6(48), eabe1508. American Association for the Advancement of Science 10.1126/sciadv.abe1508

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Epithelial calcium channel TRPV6 plays vital roles in calcium homeostasis, and its dysregulation is implicated in multifactorial diseases, including cancers. Here, we study the molecular mechanism of selective nanomolar-affinity TRPV6 inhibition by (4-phenylcyclohexyl)piperazine derivatives (PCHPDs). We use x-ray crystallography and cryo–electron microscopy to solve the inhibitor-bound structures of TRPV6 and identify two types of inhibitor binding sites in the transmembrane region: (i) modulatory sites between the S1-S4 and pore domains normally occupied by lipids and (ii) the main site in the ion channel pore. Our structural data combined with mutagenesis, functional and computational approaches suggest that PCHPDs plug the open pore of TRPV6 and convert the channel into a nonconducting state, mimicking the action of calmodulin, which causes inactivation of TRPV6 channels under physiological conditions. This mechanism of inhibition explains the high selectivity and potency of PCHPDs and opens up unexplored avenues for the design of future-generation biomimetic drugs.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Nephrologie / Hypertonie
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
08 Faculty of Science > Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP)

UniBE Contributor:

Bhardwaj, Rajesh; Rodrigues Cunha, Micael; Gyimesi, Gergely; Reymond, Jean-Louis and Hediger, Matthias

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry

ISSN:

2375-2548

Publisher:

American Association for the Advancement of Science

Language:

English

Submitter:

Sandra Tanja Zbinden Di Biase

Date Deposited:

11 Dec 2020 09:11

Last Modified:

13 Dec 2020 02:52

Publisher DOI:

10.1126/sciadv.abe1508

BORIS DOI:

10.7892/boris.148887

URI:

https://boris.unibe.ch/id/eprint/148887

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