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Identification of the PIP 2 ‐binding site on Kir6.2 by molecular modelling and functional analysis
Author(s) -
Haider Shozeb,
Tarasov Andrei I,
Craig Tim J,
Sansom Mark SP,
Ashcroft Frances M
Publication year - 2007
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601809
Subject(s) - biology , identification (biology) , binding site , computational biology , genetics , ecology
ATP‐sensitive potassium (K ATP ) channels couple cell metabolism to electrical activity by regulating K + fluxes across the plasma membrane. Channel closure is facilitated by ATP, which binds to the pore‐forming subunit (Kir6.2). Conversely, channel opening is potentiated by phosphoinositol bisphosphate (PIP 2 ), which binds to Kir6.2 and reduces channel inhibition by ATP. Here, we use homology modelling and ligand docking to identify the PIP 2 ‐binding site on Kir6.2. The model is consistent with a large amount of functional data and was further tested by mutagenesis. The fatty acyl tails of PIP 2 lie within the membrane and the head group extends downwards to interact with residues in the N terminus (K39, N41, R54), transmembrane domains (K67) and C terminus (R176, R177, E179, R301) of Kir6.2. Our model suggests how PIP 2 increases channel opening and decreases ATP binding and channel inhibition. It is likely to be applicable to the PIP 2 ‐binding site of other Kir channels, as the residues identified are conserved and influence PIP 2 sensitivity in other Kir channel family members.