Structural mechanisms of TRPM7 activation and inhibition

Kirill D. Nadezhdin, Leonor Correia, Chamali Narangoda, Dhilon S. Patel, Arthur Neuberger, Thomas Gudermann, Maria G. Kurnikova (), Vladimir Chubanov () and Alexander I. Sobolevsky ()
Additional contact information
Kirill D. Nadezhdin: Columbia University
Leonor Correia: Walther-Straub Institute of Pharmacology and Toxicology, LMU Munich
Chamali Narangoda: Carnegie Mellon University
Dhilon S. Patel: Carnegie Mellon University
Arthur Neuberger: Columbia University
Thomas Gudermann: Walther-Straub Institute of Pharmacology and Toxicology, LMU Munich
Maria G. Kurnikova: Carnegie Mellon University
Vladimir Chubanov: Walther-Straub Institute of Pharmacology and Toxicology, LMU Munich
Alexander I. Sobolevsky: Columbia University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract The transient receptor potential channel TRPM7 is a master regulator of the organismal balance of divalent cations that plays an essential role in embryonic development, immune responses, cell mobility, proliferation, and differentiation. TRPM7 is implicated in neuronal and cardiovascular disorders, tumor progression and has emerged as a new drug target. Here we use cryo-EM, functional analysis, and molecular dynamics simulations to uncover two distinct structural mechanisms of TRPM7 activation by a gain-of-function mutation and by the agonist naltriben, which show different conformational dynamics and domain involvement. We identify a binding site for highly potent and selective inhibitors and show that they act by stabilizing the TRPM7 closed state. The discovered structural mechanisms provide foundations for understanding the molecular basis of TRPM7 channelopathies and drug development.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-38362-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38362-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-38362-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().