Reassessment of the unique mode of binding between angiotensin II type 1 receptor and their blockers

Abstract

While the molecular structures of angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) are very similar, they are also slightly different. Although each ARB has been shown to exhibit a unique mode of binding to AT1 receptor, different positions of the AT1 receptor have been analyzed and computational modeling has been performed using different crystal structures for the receptor as a template and different kinds of software. Therefore, we systematically analyzed the critical positions of the AT1 receptor, Tyr(113), Tyr(184), Lys(199), His(256) and Gln(257) using a mutagenesis study, and subsequently performed computational modeling of the binding of ARBs to AT1 receptor using CXCR4 receptor as a new template and a single version of software. The interactions between Tyr(113) in the AT1 receptor and the hydroxyl group of olmesartan, between Lys(199) and carboxyl or tetrazole groups, and between His(256) or Gln(257) and the tetrazole group were studied. The common structure, a tetrazole group, of most ARBs similarly bind to Lys(199), His(256) and Gln(257) of AT1 receptor. Lys(199) in the AT1 receptor binds to the carboxyl group of EXP3174, candesartan and azilsartan, whereas oxygen in the amidecarbonyl group of valsartan may bind to Lys(199). The benzimidazole portion of telmisartan may bind to a lipophilic pocket that includes Tyr(113). On the other hand, the n-butyl group of irbesartan may bind to Tyr(113). In conclusion, we confirmed that the slightly different structures of ARBs may be critical for binding to AT1 receptor and for the formation of unique modes of binding.

Figure 1. Chemical structures of the angiotensin II type 1 receptor blockers EXP3174, which is an active metabolite of losartan, candesartan, valsartan, telmisartan, olmesartan, irbesartan and azilsartan.

Figure 2. A. Position of the second extracellular loop (ECL2) in the model of AT₁ receptor using bovine rhodopsin (orange) or CXCR4 (yellow) receptor as a template.

B. Molecular modeling of the interaction between olmesartan and the AT₁ receptor. The AT₁ receptor is shown as a ribbon and Tyr¹¹³, Lys¹⁹⁹, His²⁵⁶, Gln²⁵⁷ and olmesartan are shown as stick models. Color notation in the helix is as follows: transmembrane (TM)1, orange; TM3, yellow; TM5, dark green; TM6, blue; and TM7, purple.

Figure 3. Molecular modeling of the interactions between the 7 ARBs and the AT₁ receptor.

Color notation in the helix is as follows: transmembrane (TM)1, orange; TM2, dark yellow; TM3, yellow; TM4, green; TM5, dark green; TM6, blue; and TM7, purple.

Figure 4. Molecular modeling of a close-up view of the interactions between the 7 ARBs and the AT₁ receptor.

Color notation in the helix is as follows: transmembrane (TM)1, orange; TM3, yellow; TM5, dark green; TM6, blue; and TM7, purple.

Figure 5. Possible molecular modeling of the interactions between a lipophilic pocket (gray zone) in the AT₁ receptor and telmisartan or irbesartan.

Color notation in the helix is as follows: transmembrane (TM)3, yellow; TM5, dark green; and TM6, blue.