Critical Hydrogen Bond Formation for Activation of the Angiotensin II Type 1 Receptor

Cabana, Jérôme; Holleran, Brian J.; Beaulieu, Marie-Ève; Leduc, Richard; Escher, Emanuel; Guillemette, Gaétan; Lavigne, Pierre

doi:10.1074/jbc.m112.395939

Cited by 20 publications

(38 citation statements)

References 74 publications

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“…Since mutations of either Asn111 TM3 or Asn295 TM7 induce constitutive activation of the AT1R, the inactive conformation of AT1R was proposed to be stabilized by the H-bond between Asn111 TM3 and Asn295 TM7 , which is confirmed by the crystal structure (Zhang et al, 2015 (Cabana et al, 2013;Zhang et al, 2015). Thus, the network of interacting residues around Asn111 TM3 and Asn295…”

Section: Tm7supporting

confidence: 54%

“…Furthermore, direct structure-function studies on the AT1R have suggested both rotational and translational motion of TM2, TM3, TM5, TM6, and TM7 in the N111G-AT1R (Boucard et al, 2003;Martin et al, 2004Martin et al, , 2007Domazet et al, 2009). Based on molecular dynamics simulation studies on N111G-AT1R, an active-state H-bond network where Asp74 TM2 interacts with Asn46 TM1 and Asn295 TM7 was proposed (Cabana et al, 2013). The same authors also indicated that the N111G mutation leads to hydrating the hydrophobic core and facilitating the interaction of the toggle switch residue, Trp253 TM6 with Ala291 TM7 and Leu112 TM3 (Cabana et al, 2013).…”

Section: Molecular Mechanism Of Inverse Agonism Of At1r Blockersmentioning

confidence: 99%

“…Based on molecular dynamics simulation studies on N111G-AT1R, an active-state H-bond network where Asp74 TM2 interacts with Asn46 TM1 and Asn295 TM7 was proposed (Cabana et al, 2013). The same authors also indicated that the N111G mutation leads to hydrating the hydrophobic core and facilitating the interaction of the toggle switch residue, Trp253 TM6 with Ala291 TM7 and Leu112 TM3 (Cabana et al, 2013). All four ARBs may thus prevent stability of the Asn46-Asp74-Asn295 H-bond network and reduce hydration of the transmembrane core through their hydrophobic characteristics.…”

Section: Molecular Mechanism Of Inverse Agonism Of At1r Blockersmentioning

confidence: 99%

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Structure-Function Basis of Attenuated Inverse Agonism of Angiotensin II Type 1 Receptor Blockers for Active-State Angiotensin II Type 1 Receptor

et al. 2015

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Ligand-independent signaling by the angiotensin II type 1 receptor (AT1R) can be activated in clinical settings by mechanical stretch and autoantibodies as well as receptor mutations. Transition of the AT1R to the 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 has been understudied not only in relation to the AT1R but also regarding other homologous receptors. Here, we demonstrate that the active-state transition in the AT1R indeed attenuates an 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 (Ser109 TM3 , Phe182 ECL2 , Gln257 TM6 , Tyr292 TM7 , and Asn295 TM7 ) results in potent inverse agonism. In the activated state, the ARB-AT1R interactions shift to a different set of residues (Val108 TM3 , Ser109 TM3 , Ala163 TM4 , Phe182 ECL2 , Lys199 TM5 , Tyr292 TM7 , and Asn295 TM7 ), resulting in attenuated inverse agonism. Interestingly, V108I, A163T, N295A, and F182A mutations in the activated state of the AT1R shift the functional response to the ARB binding toward agonism, but in the ground state the same mutations cause inverse agonism. Our data show that the second extracellular loop is an important regulator of the functional states of the AT1R. Our findings suggest that the quest for discovering novel ARBs, and improving current ARBs, fundamentally depends on the knowledge of the unique sets of residues that mediate inverse agonistic potency in the two states of the AT1R.

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Section: Tm7supporting

confidence: 54%

Section: Molecular Mechanism Of Inverse Agonism Of At1r Blockersmentioning

confidence: 99%

Section: Molecular Mechanism Of Inverse Agonism Of At1r Blockersmentioning

confidence: 99%

See 1 more Smart Citation

Structure-Function Basis of Attenuated Inverse Agonism of Angiotensin II Type 1 Receptor Blockers for Active-State Angiotensin II Type 1 Receptor

et al. 2015

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“…Of particular interest is a region within the receptor identified as the major H-bond network (MHN). It is composed of several functionally important and conserved polar residues among class A GPCRs (8,9). This region has also been identified as a sodiumbinding site in some GPCRs (10,11).…”

mentioning

confidence: 99%

Identification of Distinct Conformations of the Angiotensin-II Type 1 Receptor Associated with the Gq/11 Protein Pathway and the β-Arrestin Pathway Using Molecular Dynamics Simulations

Cabana

Holleran

Leduc

et al. 2015

Journal of Biological Chemistry

Self Cite

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Background: The N111G and D74N mutations bias the AT 1 receptor for the G q/11 and ␤-arrestin pathways, respectively. Results: Structural rearrangements of theAT 1 receptor are induced by the N111G mutation and AngII. Conclusion: Activation of the G q/11 and ␤-arrestin pathways is associated with a decreased and increased stability, respectively, of the ground state of the receptor. Significance: Distinct conformations of AT 1 receptor are associated with distinct pathways.

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“…Nowadays, the latest breakthroughs in molecular dynamics simulations deal with biological processes that take place over longer timescales. For example, protein folding [18], transmembrane receptor activation [19,20] and ligand binding [21]. These simulations require substantial computer power or purpose built hardware such as Anton that pushes the current limit of MD simulations to the millisecond range [22].…”

Section: Introductionmentioning

confidence: 99%

A coarse-grained elastic network atom contact model and its use in the simulation of protein dynamics and the prediction of the effect of mutations

Frappier

Najmanovich

2013

Preprint

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Normal mode analysis (NMA) methods are widely used to study dynamic aspects of protein structures. Two critical components of NMA methods are coarse-graining in the level of simplification used to represent protein structures and the choice of potential energy functional form. There is a trade-off between speed and accuracy in different choices. In one extreme one finds accurate but slow molecular-dynamics based methods with all-atom representations and detailed atom potentials. On the other extreme, fast elastic network model (ENM) methods with C a2 only representations and simplified potentials that based on geometry alone, thus oblivious to protein sequence. Here we present ENCoM, an Elastic Network Contact Model that employs a potential energy function that includes a pairwise atom-type non-bonded interaction term and thus makes it possible to consider the effect of the specific nature of amino-acids on dynamics within the context of NMA. ENCoM is as fast as existing ENM methods and outperforms such methods in the generation of conformational ensembles. Here we introduce a new application for NMA methods with the use of ENCoM in the prediction of the effect of mutations on protein stability. While existing methods are based on machine learning or enthalpic considerations, the use of ENCoM, based on vibrational normal modes, is based on entropic considerations. This represents a novel area of application for NMA methods and a novel approach for the prediction of the effect of mutations. We compare ENCoM to a large number of methods in terms of accuracy and self-consistency. We show that the accuracy of ENCoM is comparable to that of the best existing methods. We show that existing methods are biased towards the prediction of destabilizing mutations and that ENCoM is less biased at predicting stabilizing mutations.

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Critical Hydrogen Bond Formation for Activation of the Angiotensin II Type 1 Receptor

Cited by 20 publications

References 74 publications

Structure-Function Basis of Attenuated Inverse Agonism of Angiotensin II Type 1 Receptor Blockers for Active-State Angiotensin II Type 1 Receptor

Structure-Function Basis of Attenuated Inverse Agonism of Angiotensin II Type 1 Receptor Blockers for Active-State Angiotensin II Type 1 Receptor

Identification of Distinct Conformations of the Angiotensin-II Type 1 Receptor Associated with the Gq/11 Protein Pathway and the β-Arrestin Pathway Using Molecular Dynamics Simulations

A coarse-grained elastic network atom contact model and its use in the simulation of protein dynamics and the prediction of the effect of mutations

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