RT Journal Article
SR Electronic
T1 Structure-function Basis of Attenuated Inverse Agonism of ARBs for Active-state AT1 Receptor
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.115.099176
DO 10.1124/mol.115.099176
A1 Takanobu Takezako
A1 Hamiyet Unal
A1 Sadashiva S Karnik
A1 Koichi Node
YR 2015
UL http://molpharm.aspetjournals.org/content/early/2015/07/06/mol.115.099176.abstract
AB Ligand-independent signaling by the angiotensin II (Ang II) type 1 receptor (AT1R) can be activated in clinical setting by mechanical stretch and auto-antibodies as well as receptor mutations. Transition of AT1R to activated state is known to lower inverse agonistic efficacy of clinically used AT1R blockers (ARBs). The structure-function basis for reduced efficacy of inverse agonists is a fundamental aspect that is under studied not only for AT1R but also other homologous receptors. Here we demonstrate that active-state transition in AT1R indeed attenuates inverse agonistic effect of four biphenyl-tetrazole ARBs through changes in specific ligand-receptor interactions. In the ground state, tight interactions of four ARBs with a set of residues, Ser109TM3, Phe182ECL2, Gln257TM6, Tyr292TM7 and Asn295TM7 results in potent inverse agonism. In the activated state, the ARB-AT1R interactions shift to a different set of residues, Val108TM3, Ser109TM3, Ala163TM4, Phe182ECL2, Lys199TM5, Tyr292TM7 and Asn295TM7 resulting in attenuated inverse agonism. Interestingly, V108I, A163T, N295A and F182A mutations in the activated state of AT1R shift functional response to ARB binding toward agonism but in the ground state same mutations cause inverse agonism. Our data show that the second extracellular loop is an important regulator of functional states of AT1R. Our findings suggest that quest for discovering novel and improving current ARBs fundamentally depends on the knowledge of unique sets of residues that mediate inverse agonistic potency in the two states of AT1R.