6MJ2

Human TRPM2 ion channel in a calcium- and ADPR-bound state

Summary for 6MJ2

• Entry DOI: 10.2210/pdb6mj2/pdb
• Related: 6MIX 6MIZ 6MJ2
• EMDB information: 9132 9133 9134
• Descriptor: Transient receptor potential cation channel subfamily M member 2, CALCIUM ION (2 entities in total)
• Functional Keywords: channel, membrane protein, trpm2, trp, adpr, adp-ribose, nudt9h, nudt9, calcium, ion channel
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 685825.06

Authors

Wang, L.,Fu, T.M.,Xia, S.,Wu, H. (deposition date: 2018-09-20, release date: 2018-12-12, Last modification date: 2024-10-09)

Primary citation

Wang, L.,Fu, T.M.,Zhou, Y.,Xia, S.,Greka, A.,Wu, H.
Structures and gating mechanism of human TRPM2.
Science, 362:-, 2018

PubMed Abstract: Transient receptor potential (TRP) melastatin 2 (TRPM2) is a cation channel associated with numerous diseases. It has a C-terminal NUDT9 homology (NUDT9H) domain responsible for binding adenosine diphosphate (ADP)-ribose (ADPR), and both ADPR and calcium (Ca) are required for TRPM2 activation. Here we report cryo-electron microscopy structures of human TRPM2 alone, with ADPR, and with ADPR and Ca NUDT9H forms both intra- and intersubunit interactions with the N-terminal TRPM homology region (MHR1/2/3) in the apo state but undergoes conformational changes upon ADPR binding, resulting in rotation of MHR1/2 and disruption of the intersubunit interaction. The binding of Ca further engages transmembrane helices and the conserved TRP helix to cause conformational changes at the MHR arm and the lower gating pore to potentiate channel opening. These findings explain the molecular mechanism of concerted TRPM2 gating by ADPR and Ca and provide insights into the gating mechanism of other TRP channels.

PubMed: 30467180
DOI: 10.1126/science.aav4809

Experimental method

ELECTRON MICROSCOPY (6.36 Å)