Moore Graham J, Ridgway Harry, Gadanec Laura Kate, Apostolopoulos Vasso, Zulli Anthony, Matsoukas John M
Pepmetics Inc., 772 Murphy Place, Victoria, BC V6Y 3H4, Canada.
THERAmolecular, LLC, Rodeo, NM 88056, USA.
Molecules. 2025 May 30;30(11):2399. doi: 10.3390/molecules30112399.
For the interaction of angiotensin II (AngII) with AngII type 1 receptors (ATR), two potential proton hopping pathways have been identified, each associated with distinct physiological outcomes. The octapeptide AngII (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) appears to form a charge relay system (CRS) in solution in which the C-terminal carboxylate abstracts a proton from the His imidazole group, which, in turn, abstracts a proton from the Tyr hydroxyl (OH) group, creating a tyrosinate anion. When AngII binds to the ATR, the CRS can be reconstituted with D281 of the receptor taking up the role of the Phe carboxylate in the tripartite interaction, whilst the Phe carboxylate forms a salt bridge with K199 of the receptor. As a consequence, the Tyr OH of AngII is positioned with accessibility to either the Phe carboxylate (bound to K199) or the His imidazole (activated by D281), thereby creating a potential gating mechanism for ATR receptor signaling. This study summarizes evidence based on structure activity data for various analogs wherein Tyr OH interaction with His imidazole (CRS formation) leads to G protein sequestration and vasoconstriction, whereas Tyr OH interaction with Phe carboxylate (bound to K199) engenders arrestin-mediated vasodilation and receptor desensitization. These findings, combined with quantum mechanical (semiempirical) calculations of CRS proton transfer presented herein, provide insights for the therapeutic targeting of angiotensin receptor blockers (sartans) and the development of second-generation drugs (bisartans).
对于血管紧张素II（AngII）与1型血管紧张素II受体（ATR）的相互作用，已确定了两条潜在的质子跳跃途径，每条途径都与不同的生理结果相关。八肽AngII（天冬氨酸-精氨酸-缬氨酸-酪氨酸-异亮氨酸-组氨酸-脯氨酸-苯丙氨酸）在溶液中似乎形成了一个电荷中继系统（CRS），其中C端羧酸盐从组氨酸咪唑基团夺取一个质子，该咪唑基团继而从酪氨酸羟基（OH）夺取一个质子，形成酪氨酸阴离子。当AngII与ATR结合时，CRS可以重新构建，受体的D281承担三方相互作用中苯丙氨酸羧酸盐的角色，而苯丙氨酸羧酸盐与受体的K199形成盐桥。因此，AngII的酪氨酸OH可接近与K199结合的苯丙氨酸羧酸盐或被D281激活的组氨酸咪唑，从而为ATR受体信号传导创造了一种潜在的门控机制。本研究总结了基于各种类似物的结构活性数据的证据，其中酪氨酸OH与组氨酸咪唑的相互作用（CRS形成）导致G蛋白隔离和血管收缩，而酪氨酸OH与苯丙氨酸羧酸盐（与K199结合）的相互作用则引发抑制蛋白介导的血管舒张和受体脱敏。这些发现，结合本文提出的CRS质子转移的量子力学（半经验）计算，为血管紧张素受体阻滞剂（沙坦类）的治疗靶点和第二代药物（双沙坦类）的开发提供了见解。
