6PUR

Human TRPM2 bound to ADPR

Summary for 6PUR

• Entry DOI: 10.2210/pdb6pur/pdb
• EMDB information: 20478 20479 20480 20482
• Descriptor: Transient receptor potential cation channel subfamily M member 2, ADENOSINE-5-DIPHOSPHORIBOSE (2 entities in total)
• Functional Keywords: trpm2 channel, adpr, transport protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 693594.78

Authors

Du, J.,Lu, W.,Huang, Y. (deposition date: 2019-07-18, release date: 2019-09-25, Last modification date: 2024-03-20)

Primary citation

Huang, Y.,Roth, B.,Lu, W.,Du, J.
Ligand recognition and gating mechanism through three ligand-binding sites of human TRPM2 channel.
Elife, 8:-, 2019

PubMed Abstract: TRPM2 is critically involved in diverse physiological processes including core temperature sensing, apoptosis, and immune response. TRPM2's activation by Ca 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 Ca 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.

PubMed: 31513012
DOI: 10.7554/eLife.50175

Experimental method

ELECTRON MICROSCOPY (4.4 Å)