挥发性全麻药作用机制的变构理论

The allosteric mechanisms of volatile anesthetic action

背景挥发性全麻药（volatileanesthetics，VAs）对蛋白质功能的调节机制是分子药理学面临的巨大挑战。总体证据显示VAs是通过影响变构（如干扰闸门）的方式而非竞争（如与配体结合位点直接相互作用）的方式调节离子通道的功能。目的对挥发性全麻药作用机制的变构理论作一综述。内容VAs异氟烷与淋巴细胞功能相关抗原-1（1ymphocytefunction—associatedantigen一1，LFA-1）配体结合区复合体的高分辨力晶体结构，首次详尽地揭示了VAs与已经确认的变构腔（在整体蛋白激活与失活状态之间的构象转换中起关键作用）结合的原子景象，而在这个配体结合区内异氟烷结合位点发生的一系列两性分子的相互作用，与以前在蛋白质模型中通过x晶体法观察到的假定的“麻醉药共同结合模式”非常一致，提示这种对蛋白质功能的变构调节机制可能与其在中枢神经系统（centralnervoussystem，CNS）离子通道相互作用的机制相同。趋势VAs的变构调节方式可能在CNS的特定靶位得到证实。

Background The mechanism by which volatile anesthetics （VAs） modulate protein activity is one of the major challenges facing molecular pharmacology. Accumulating biochemical evidence demonstrates that VAs modulate ion channel functions in an allosterie mode （i.e. perturbation of the gating machinery）, as opposed to a competitive mode （i.e. direct interaction with the ligand binding site）. Objective To review the allosteric mechanism of VAs action. Content The high-resolution crystal structure of the lymphocyte function-associated antigen-1 （LFA-1） domain in complex with the VAs isoflurane reveals, for the first time, a detailed atomic view of VAs binding to the well-established allosteric pocket critical for conformational transition of the integrin between an active and an inactive state. The isoflurane binding site within the LFA-1 domain involves an array of amphiphilic interactions and correlates remarkably well with a postulated ＂common anesthetic binding motif＂ observed in model proteins examined by X-ray crystallography. These results suggest that the mechanisms underlying the allosteric modulation of protein function might be generalized to VAs-ion channel interactions in the central nervous system （CNS）. Trend The allosteric modulation of VAs may be verified by high-resolution crystal structures of these CNS targets bound to VA.