Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2.

摘要: The regulation of ion channel activity by specific lipid molecules is widely recognized as an integral component electrical signalling in cells. In particular, phosphatidylinositol 4,5-bisphosphate (PIP(2)), a minor yet dynamic phospholipid cell membranes, known to regulate many different channels. PIP(2) the primary agonist for classical inward rectifier (Kir2) channels, through which this can cell's resting membrane potential. However, molecular mechanism exerts its action unknown. Here we present X-ray crystal structure Kir2.2 complex with short-chain (dioctanoyl) derivative PIP(2). We found that binds at interface between transmembrane domain (TMD) and cytoplasmic (CTD). PIP(2)-binding site consists conserved non-specific phospholipid-binding region TMD phosphatidylinositol-binding CTD. On binding, flexible expansion linker contracts compact helical structure, CTD translates 6 A becomes tethered inner helix gate begins open. contrast, small anionic dioctanoyl glycerol pyrophosphatidic acid (PPA) also region, but not thus fails engage or open channel. Our results show how control potential ion-channel-receptor-ligand interaction brings about large conformational change, analogous neurotransmitter activation channels synapses.