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Comparative structural biology of human and opossum AT 1 Rs reveals different ARB binding sites
Author(s) -
Chandler Andrew,
Kurita Tomomi,
Alsamarah Abdelaziz,
Kanassatega RhyeSamuel,
Luo Yun,
Andresen Bradley
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.971.1
Subject(s) - moiety , chemistry , valsartan , opossum , docking (animal) , stereochemistry , binding site , biochemistry , biology , medicine , endocrinology , nursing , anatomy , blood pressure
Angiotensin II type 1 receptors (AT 1 Rs) are involved in numerous physiological processes and AT 1 R competitive antagonists (ARBs) are used widely as treatments for cardiovascular diseases. However, not all patients, nor species, respond equally to ARBs presumably due to alterations within the ARB binding pocket. Previous studies indicate that the opossum (o) AT 1 R does not bind, or binds with very low affinity, to ARBs containing a di‐benzyl and five membered ring heterocycle moiety, such as valsartan, due to an altered ARB binding pocket. Thus, the oAT 1 R can serve as a model of ARB resistance, and an experimentally validated control for elucidating the binding sites of each ARB. AT 1 R models were prepared and simulated using explicit water solvent and equilibrated for 100 ns. To test the hypothesis that structurally unique ARBs bind to unique sites, each clinically viable ARB was docked to the final eleven configurations of molecular dynamics equilibrated inactive human (h) AT 1 R and oAT 1 R. Initial docking of valsartan confirmed the experimental data showing a lack of affinity for the oAT 1 R (‐0.28 ± 2.72 kcal/mol compared to ‐8.12 ± 0.77 kcal/mol for the hAT 1 R, n = 10). Surprisingly, ARBs lacking this moiety bound to a different site with reasonable affinity in both oAT 1 R and hAT 1 R models (‐6.29 ± 0.44 and ‐7.19 ± 0.63 kcal/mol, respectively). These data suggest that resistance to valsartan, the most commonly prescribed ARB, may not translate to a general ARB resistance. Furthermore, ARBs lacking the di‐benzyl and pentameric ring moiety, such as eprosartan, may be more efficacious in “ARB‐resistant” patients.