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Ligand recognition and gating mechanism through three ligand-binding sites of human TRPM2 channel.

<div class='caption-title'>The overall architecture of hsTRPM2.</div>
Figure 1—figure supplement 1.
<div class='caption-title'>Cryo-EM data analysis of hsTRPM2.</div>
Huang Y, Roth B, Lü W, Du J
OpenAccess logo Elife 8 (2019)
Related entries: 6puo, 6pus, 6puu

Cited: 52 times
EuropePMC logo PMID: 31513012

Abstract

TRPM2 is critically involved in diverse physiological processes including core temperature sensing, apoptosis, and immune response. TRPM2's activation by Ca2+ and ADP ribose (ADPR), an NAD+-metabolite produced under oxidative stress and neurodegenerative conditions, suggests a role in neurological disorders. We provide a central concept between triple-site ligand binding and the channel gating of human TRPM2. We show consecutive structural rearrangements and channel activation of TRPM2 induced by binding of ADPR in two indispensable locations, and the binding of Ca2+ in the transmembrane domain. The 8-Br-cADPR-an antagonist of cADPR-binds only to the MHR1/2 domain and inhibits TRPM2 by stabilizing the channel in an apo-like conformation. We conclude that MHR1/2 acts as a orthostatic ligand-binding site for TRPM2. The NUDT9-H domain binds to a second ADPR to assist channel activation in vertebrates, but not necessary in invertebrates. Our work provides insights into the gating mechanism of human TRPM2 and its pharmacology.

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  2. Structural Pharmacology of TRP Channels. Zhao Y, McVeigh BM, Moiseenkova-Bell VY. J Mol Biol 433 166914 (2021)
  3. Structure-Function Relationship of TRPM2: Recent Advances, Contradictions, and Open Questions. Kühn FJP. Int J Mol Sci 21 E6481 (2020)
  4. Two Decades of Evolution of Our Understanding of the Transient Receptor Potential Melastatin 2 (TRPM2) Cation Channel. Szollosi A. Life (Basel) 11 397 (2021)

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  4. The Role of cAMP in Beta Cell Stimulus-Secretion and Intercellular Coupling. Stožer A, Paradiž Leitgeb E, Pohorec V, Dolenšek J, Križančić Bombek L, Gosak M, Skelin Klemen M. Cells 10 1658 (2021)
  5. Current View of Ligand and Lipid Recognition by the Menthol Receptor TRPM8. Yin Y, Lee SY. Trends Biochem Sci 45 806-819 (2020)
  6. Does Cyclic ADP-Ribose (cADPR) Activate the Non-selective Cation Channel TRPM2? Fliegert R, Riekehr WM, Guse AH. Front Immunol 11 2018 (2020)
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  18. The transient receptor potential melastatin 2: a new therapeutical target for Parkinson's disease? Ferreira AFF, Britto LRG. Neural Regen Res 18 1652-1656 (2023)

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