TY - JOUR
T1 - Trapping of spermine, Kukoamine A, and polyamine toxin blockers in GluK2 kainate receptor channels
AU - Gangwar, Shanti Pal
AU - Yelshanskaya, Maria V.
AU - Aktolun, Muhammed
AU - Yen, Laura Y.
AU - Newton, Thomas P.
AU - Strømgaard, Kristian
AU - Kurnikova, Maria G.
AU - Sobolevsky, Alexander I.
N1 - Funding Information:
We thank Robert Grassucci and Zhening Zhang (Columbia University Cryo-Electron Microscopy Center), Gabriella Angiulli (New York Structural Biology Center/ National Center for CryoEM Access and Training), Patrick Mitchell, Ian Fries (Stanford Linear Accelerator Center/National Accelerator Laboratory) and Sean Mulligan (Pacific Northwest cryo-EM Center (PNCC) for help with microscope operation and data collection. Some of this work was performed at the Columbia University Cryo-Electron Microscopy Center. A portion of this research was supported by NIH grant U24GM129547 and performed at the PNCC at OHSU and accessed through EMSL (grid.436923.9), a DOE Office of Science User Facility sponsored by the Office of Biological and Environmental Research. Some of this work was performed at the National Center for CryoEM Access and Training (NCCAT) and the Simons Electron Microscopy Center located at the New York Structural Biology Center, supported by the NIH Common Fund Transformative High Resolution Cryo-Electron Microscopy program (U24 GM129539) and by grants from the Simons Foundation (SF349247) and NY State Assembly Majority. Some of this work was performed at the Stanford-SLAC Cryo-EM Center (S2C2), supported by the National Institutes of Health Common Fund Transformative High Resolution Cryo-Electron Microscopy program (U24 GM129541). S.P.G. was supported by the NIH (NS139087).\u00A0A.I.S. was supported by the NIH (NS083660, NS107253, AR078814, CA206573). M.G.K. was supported by the NSF MCB-1818213 and grant of time XSEDE NSF MCB180173.
Funding Information:
We thank Robert Grassucci and Zhening Zhang (Columbia University Cryo-Electron Microscopy Center), Gabriella Angiulli (New York Structural Biology Center/ National Center for CryoEM Access and Training), Patrick Mitchell, Ian Fries (Stanford Linear Accelerator Center/National Accelerator Laboratory) and Sean Mulligan (Pacific Northwest cryo-EM Center (PNCC) for help with microscope operation and data collection. Some of this work was performed at the Columbia University Cryo-Electron Microscopy Center. A portion of this research was supported by NIH grant U24GM129547 and performed at the PNCC at OHSU and accessed through EMSL (grid.436923.9), a DOE Office of Science User Facility sponsored by the Office of Biological and Environmental Research. Some of this work was performed at the National Center for CryoEM Access and Training (NCCAT) and the Simons Electron Microscopy Center located at the New York Structural Biology Center, supported by the NIH Common Fund Transformative High Resolution Cryo-Electron Microscopy program (U24 GM129539) and by grants from the Simons Foundation (SF349247) and NY State Assembly Majority. Some of this work was performed at the Stanford-SLAC Cryo-EM Center (S2C2), supported by the National Institutes of Health Common Fund Transformative High Resolution Cryo-Electron Microscopy program (U24 GM129541). S.P.G. was supported by the NIH (NS139087). A.I.S. was supported by the NIH (NS083660, NS107253, AR078814, CA206573). M.G.K. was supported by the NSF MCB-1818213 and grant of time XSEDE NSF MCB180173.
Publisher Copyright:
© The Author(s) 2024.
PY - 2024
Y1 - 2024
N2 - Kainate receptors (KARs) are a subtype of ionotropic glutamate receptor (iGluR) channels, a superfamily of ligand-gated ion channels which mediate the majority of excitatory neurotransmission in the central nervous system. KARs modulate neuronal circuits and plasticity during development and are implicated in neurological disorders, including epilepsy, depression, schizophrenia, anxiety, and autism. Calcium-permeable KARs undergo ion channel block, but the therapeutic potential of channel blockers remains underdeveloped, mainly due to limited structural knowledge. Here, we present closed-state structures of GluK2 KAR homotetramers in complex with ion channel blockers NpTx-8, PhTx-74, Kukoamine A, and spermine. We find that blockers reside inside the GluK2 ion channel pore, intracellular to the closed M3 helix bundle-crossing gate, with their hydrophobic heads filling the central cavity and positively charged polyamine tails spanning the selectivity filter. Molecular dynamics (MD) simulations of our structures illuminate interactions responsible for different affinity and binding poses of the blockers. Our structures elucidate the trapping mechanism of KAR channel block and provide a template for designing new blockers that can selectively target calcium-permeable KARs in neuropathologies.
AB - Kainate receptors (KARs) are a subtype of ionotropic glutamate receptor (iGluR) channels, a superfamily of ligand-gated ion channels which mediate the majority of excitatory neurotransmission in the central nervous system. KARs modulate neuronal circuits and plasticity during development and are implicated in neurological disorders, including epilepsy, depression, schizophrenia, anxiety, and autism. Calcium-permeable KARs undergo ion channel block, but the therapeutic potential of channel blockers remains underdeveloped, mainly due to limited structural knowledge. Here, we present closed-state structures of GluK2 KAR homotetramers in complex with ion channel blockers NpTx-8, PhTx-74, Kukoamine A, and spermine. We find that blockers reside inside the GluK2 ion channel pore, intracellular to the closed M3 helix bundle-crossing gate, with their hydrophobic heads filling the central cavity and positively charged polyamine tails spanning the selectivity filter. Molecular dynamics (MD) simulations of our structures illuminate interactions responsible for different affinity and binding poses of the blockers. Our structures elucidate the trapping mechanism of KAR channel block and provide a template for designing new blockers that can selectively target calcium-permeable KARs in neuropathologies.
U2 - 10.1038/s41467-024-54538-x
DO - 10.1038/s41467-024-54538-x
M3 - Journal article
C2 - 39592599
AN - SCOPUS:85210392354
SN - 2041-1723
VL - 15
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 10257
ER -