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Use of a Molecular Switch Probe to Activate or Inhibit GIRK1 Heteromers In Silico Reveals a Novel Gating Mechanism
- Source :
- International Journal of Molecular Sciences; Volume 23; Issue 18; Pages: 10820
- Publication Year :
- 2022
- Publisher :
- Multidisciplinary Digital Publishing Institute, 2022.
-
Abstract
- G protein-gated inwardly rectifying K+ (GIRK) channels form highly active heterotetramers in the body, such as in neurons (GIRK1/GIRK2 or GIRK1/2) and heart (GIRK1/GIRK4 or GIRK1/4). Based on three-dimensional atomic resolution structures for GIRK2 homotetramers, we built heterotetrameric GIRK1/2 and GIRK1/4 models in a lipid bilayer environment. By employing a urea-based activator ML297 and its molecular switch, the inhibitor GAT1587, we captured channel gating transitions and K+ ion permeation in sub-microsecond molecular dynamics (MD) simulations. This allowed us to monitor the dynamics of the two channel gates (one transmembrane and one cytosolic) as well as their control by the required phosphatidylinositol bis 4-5-phosphate (PIP2). By comparing differences in the two trajectories, we identify three hydrophobic residues in the transmembrane domain 1 (TM1) of GIRK1, namely, F87, Y91, and W95, which form a hydrophobic wire induced by ML297 and de-induced by GAT1587 to orchestrate channel gating. This includes bending of the TM2 and alignment of a dipole of two acidic GIRK1 residues (E141 and D173) in the permeation pathway to facilitate K+ ion conduction. Moreover, the TM movements drive the movement of the Slide Helix relative to TM1 to adjust interactions of the CD-loop that controls the gating of the cytosolic gate. The simulations reveal that a key basic residue that coordinates PIP2 to stabilize the pre-open and open states of the transmembrane gate flips in the inhibited state to form a direct salt-bridge interaction with the cytosolic gate and destabilize its open state.
- Subjects :
- GIRK1 heterotetramer
ML297
MD simulations
PIP2
TM1 hydrophobic wire
Organic Chemistry
Lipid Bilayers
General Medicine
Phosphatidylinositols
Catalysis
Computer Science Applications
Phosphates
Inorganic Chemistry
G Protein-Coupled Inwardly-Rectifying Potassium Channels
GTP-Binding Proteins
Urea
Physical and Theoretical Chemistry
Molecular Biology
Ion Channel Gating
Spectroscopy
Subjects
Details
- Language :
- English
- ISSN :
- 14220067
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences; Volume 23; Issue 18; Pages: 10820
- Accession number :
- edsair.doi.dedup.....0edfbc3c55952300f51916147907f7ec
- Full Text :
- https://doi.org/10.3390/ijms231810820