Tikhonov Denis B, Bruhova Iva, Zhorov Boris S
Department of Biochemistry and Biomedical Sciences, McMaster University, 1200 Main Street West, Hamilton, Ont., Canada L8N 3Z5.
FEBS Lett. 2006 Nov 13;580(26):6027-32. doi: 10.1016/j.febslet.2006.10.035. Epub 2006 Oct 24.
Molecular modeling predicts that a local anesthetic (LA) lidocaine binds to the resting and open Na(v)1.5 in different modes, interacting with LA-sensing residues known from experiments. Besides the major pathway via the open activation gate, LAs can reach the inner pore via a "sidewalk" between D3S6, D4S6, and D3P. The ammonium group of a cationic LA binds in the focus of the pore-helices macrodipoles, which also stabilize a Na(+) ion chelated by two benzocaine molecules. The LA's cationic group and a Na(+) ion in the selectivity filter repel each other suggesting that the Na(+) depletion upon slow inactivation would stabilize a LA, while a LA would stabilize slow-inactivated states.
分子建模预测，局部麻醉药（LA）利多卡因以不同模式与静息态和开放态的Na(v)1.5结合，并与实验中已知的LA感知残基相互作用。除了通过开放激活门的主要途径外，局部麻醉药还可以通过D3S6、D4S6和D3P之间的“人行道”到达内孔。阳离子局部麻醉药的铵基团结合在孔螺旋大偶极的焦点处，该焦点也稳定了由两个苯佐卡因分子螯合的Na(+)离子。局部麻醉药的阳离子基团与选择性过滤器中的Na(+)离子相互排斥，这表明缓慢失活时Na(+)的耗尽会使局部麻醉药稳定，而局部麻醉药会稳定缓慢失活状态。
