PUFA modulation of ASIC3 involves both specific and lipid solvent-like interactions
Roth, R.; Bandarupalli, R.; Klipp, R. C.; Li, J.; Bankston, J. R.
Show abstract
Inflammatory mediators including polyunsaturated fatty acids (PUFAs) are known to potentiate ASIC3 by inducing changes in multiple gating features, yet the molecular basis for their interactions remains poorly defined. Using all-atom MD simulations and electrophysiology, we show that DHA accumulates around ASIC3 through loosely coordinated interactions with a membrane-facing electropositive region along the outer leaflet of TM1. In the open state, the carboxylate head group strongly binds to a critical arginine (R63) along with nearby polar residues that are necessary to slow the rate in channel desensitization rate but not to increase the pH sensitivity for channel activation. Moreover, mutating R63 disrupted effects on ASIC3 desensitization induced by PUFAs but not N-acyl amino acids (NAAAs) or lysophosphatidylcholines (LPCs). Our results provide the first detailed description of a functional PUFA binding site on ASICs, offering new insights into lipid modulation and potential strategies for developing novel therapeutics for pain and inflammation.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- From head to tail - Atomistic mechanism of long-range coupling from the cytosolic sensor domain to the selectivity filter in TREK K2P channels 96%
- TMEM63 proteins act as mechanically-activated cholesterol modulated lipid scramblases contributing to membrane mechano-resilience 96%
- Lipid dependence of connexin-32 gap junction channel conformations 95%
Similar papers in this journal
- Proline substitutions in the ASIC1 β11-12 linker slow desensitization 96%
- Structural Basis for Voltage Gating and Dalfampridine Binding in the Shaker Potassium Channel Revealed by Closed-State Model 95%
- Dynamic conformational changes of acid-sensing ion channels in different desensitizing conditions 94%
Similar papers in this journal
- Direct Binding of Phosphatidylglycerol at Specific Sites Modulates Desensitization of a Pentameric Ligand-Gated Ion Channel 95%
- β11-12 linker isomerization governs Acid-sensing ion channel desensitization and recovery 95%
- Mechanistic insights into robust cardiac IKs potassium channel activation by aromatic polyunsaturated fatty acid analogues 95%
Similar papers in this journal
- CONSTITUTIVE OPENING OF THE Kv7.2 PORE ACTIVATION GATE CAUSES KCNQ2-DEVELOPMENTAL ENCEPHALOPATHY 96%
- A Network of Phosphatidylinositol 4,5-bisphosphate Binding Sites Regulate Gating of the Ca2+-activated Cl- Channel ANO1 (TMEM16A) 95%
- The BK channel-NS1619 agonist complex reveals molecular insights on allosteric activation gating 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.