Unique “delta lock” structure of telmisartan is involved in its strongest binding affinity to angiotensin II type 1 receptor

Ohno, Kazuki; Amano, Y.; Kakuta, Hirotoshi; Niimi, Tatsuya; Takakura, Shoji; Orita, Masaya; Miyata, Keiji; Sakashita, Hideaki; Takeuchi, Makoto; Komuro, Issei; Higaki, Jitsuo; Horiuchi, Masatsugu; Kim‐Mitsuyama, Shokei; Mori, Yutaka; Morishita, Ryuichi; Yamagishi, Sho Ichi

doi:10.1016/j.bbrc.2010.11.139

Cited by 34 publications

(31 citation statements)

References 14 publications

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“…these residues (Ji et al 1994, Ohno et al 2011, Imaizumi et al 2013. The hydroxyl and carboxyl groups in the imidazole and the tetrazole group in the biphenyl moiety of olmesartan interact with Lys112, Tyr113, Lys199, His256, and Gln257 in the AT 1 receptor (Imaizumi et al 2013).…”

Section: Non-peptide Antagonists Binding Of the At 1 Receptormentioning

confidence: 99%

“…Telmisartan, unique among ARBs in its pharmacologic and pharmacokinetic properties (Wienen et al 2000, Cianchetti et al 2008, Zídek et al 2013, binds firmly with the AT 1 receptor through a unique 'delta lock' structure (Ohno et al 2011). The molecular modeling by Ohno et al (2011) demonstrates that the high affinity of telmisartan to the AT 1 receptor involves three distinct moieties in the structure (Fig. 2).…”

Section: Non-peptide Antagonists Binding Of the At 1 Receptormentioning

confidence: 99%

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Structural determinants for binding, activation, and functional selectivity of the angiotensin AT1 receptor

Balakumar¹,

Jagadeesh²

2014

Journal of Molecular Endocrinology

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The renin-angiotensin system (RAS) plays an important role in the pathophysiology of cardiovascular disorders. Pharmacologic interventions targeting the RAS cascade have led to the discovery of renin inhibitors, angiotensin-converting enzyme inhibitors, and AT 1 receptor blockers (ARBs) to treat hypertension and some cardiovascular and renal disorders. Mutagenesis and modeling studies have revealed that differential functional outcomes are the results of multiple active states conformed by the AT 1 receptor upon interaction with angiotensin II (Ang II). The binding of agonist is dependent on both extracellular and intramembrane regions of the receptor molecule, and as a consequence occupies more extensive area of the receptor than a non-peptide antagonist. Both agonist and antagonist bind to the same intramembrane regions to interfere with each other's binding to exhibit competitive, surmountable interaction. The nature of interactions with the amino acids in the receptor is different for each of the ARBs given the small differences in the molecular structure between drugs. AT 1 receptors attain different conformation states after binding various Ang II analogues, resulting in variable responses through activation of multiple signaling pathways. These include both classical and non-classical pathways mediated through growth factor receptor transactivations, and provide cross-communication between downstream signaling molecules. The structural requirements for AT 1 receptors to activate extracellular signal-regulated kinases 1 and 2 through G proteins, or G proteinindependently through b-arrestin, are different. We review the structural and functional characteristics of Ang II and its analogs and antagonists, and their interaction with amino acid residues in the AT 1 receptor.

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Section: Non-peptide Antagonists Binding Of the At 1 Receptormentioning

confidence: 99%

Section: Non-peptide Antagonists Binding Of the At 1 Receptormentioning

confidence: 99%

Structural determinants for binding, activation, and functional selectivity of the angiotensin AT1 receptor

Balakumar¹,

Jagadeesh²

2014

Journal of Molecular Endocrinology

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“…It has a high affinity for angiotensin II receptor type 1 (AT1), with a binding affinity 3,000 times higher for AT1 than receptor type 2 (AT2) (20). In Marfan syndrome, symptoms such as aneurysms and emphysema reflect excessive TGF-␤ signaling (13).…”

Section: Discussionmentioning

confidence: 99%

“…From a dental point of view, it is essential to determine the effect of ARBs on the progression of periodontitis. Among ARBs, telmisartan has the longest half-life of any ARB and has 3,000 times higher binding affinity to AT1 than to AT2 (18)(19)(20). In this study, we took advantage of the drug action of telmisartan and examined its effect on the experimental periodontitis model.…”

mentioning

confidence: 99%

Effect of Angiotensin II Receptor Blocker on Experimental Periodontitis in a Mouse Model of Marfan Syndrome

Suda

Moriyama

Ganburged³

2013

Infect Immun

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Marfan syndrome is an autosomal dominant disease characterized by aneurysm and dilatation of the aortic root, tall stature, and ectopia lentis. These manifestations reflect excessive signaling of transforming growth factor beta (TGF-␤). Moreover, cases are frequently associated with severe periodontitis, which is a chronic inflammation of the gingiva, periodontal ligament, and alveolar bone. Recently, angiotensin II receptor blockers (ARBs) were discovered to be an effective drug class that can prevent aortic aneurysm and dilation in Marfan syndrome by inhibiting TGF-␤ signaling. To investigate the effect of ARB on the progression of periodontitis, the application of a potent ARB, telmisartan, was examined in a mouse model of Marfan syndrome (Mg⌬). Six-week-old male heterozygous Mg⌬ and wild-type mice were challenged with Porphyromonas gingivalis, which causes chronic periodontitis, with and without telmisartan application. After infection, alveolar bone resorption was measured by micro-computed tomography (CT), and inflammatory cytokine levels were examined. Infection of Porphyromonas gingivalis induced alveolar bone resorption in both Mg⌬ and wild-type mice. The amount of resorption was significantly larger in the former than the latter. Immunoarray and enzyme-linked immunosorbent assay (ELISA) analyses demonstrated that interleukin-17 (IL-17) and tumor necrosis factor alpha (TNF-␣) levels were significantly higher in infected Mg⌬ mice than infected wild-type mice. Telmisartan treatment significantly suppressed the alveolar bone resorption of infected Mg⌬ mice. Telmisartan also significantly decreased levels of TGF-␤, IL-17, and TNF-␣ in infected Mg⌬ mice to levels seen in infected wild-type mice. This study suggests that ARB can prevent the severe periodontitis frequently seen in Marfan syndrome.

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“…7 Previously, we investigated the molecular basis of angiotensin II type 1 receptor inhibition by telmisartan using a molecular simulation and proposed a unique 'delta lock' structure for telmisartan that may be responsible for its high-binding affinity to angiotensin II type 1 receptor, thereby leading to its superiority over other ARBs in halting cardiovascular disease in patients with hypertension. 8 Recently a subgroup of ARBs was reported to induce peroxisome proliferator-activated receptor-gamma (PPARg) activity, among which telmisartan shows the strongest ability. 9,10 PPARg is the most abundant isoform in adipose tissue and has an important role in the regulation of insulin sensitivity.…”

Section: Introductionmentioning

confidence: 99%

Structural basis for telmisartan-mediated partial activation of PPAR gamma

et al. 2012

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Telmisartan, a selective angiotensin II type 1 receptor blocker, has recently been shown to act as a partial agonist for peroxisome proliferator-activated receptor gamma (PPARc). To understand how telmisartan partially activates PPARc, we determined the ternary complex structure of PPARc, telmisartan, and a coactivator peptide from steroid receptor coactivator-1 at a resolution of 2.18 Å . Crystallographic analysis revealed that telmisartan exhibits an unexpected binding mode in which the central benzimidazole ring is engaged in a non-canonical-and suboptimal-hydrogen-bonding network around helix 12 (H12). This network differs greatly from that observed when full-agonists bind with PPARc and prompt high-coactivator recruitment through H12 stabilized by multiple hydrogen bonds. Binding with telmisartan results in a less stable H12 that in turn leads to attenuated coactivator binding, thus explaining the mechanism of partial activation.

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Unique “delta lock” structure of telmisartan is involved in its strongest binding affinity to angiotensin II type 1 receptor

Cited by 34 publications

References 14 publications

Structural determinants for binding, activation, and functional selectivity of the angiotensin AT1 receptor

Structural determinants for binding, activation, and functional selectivity of the angiotensin AT1 receptor

Effect of Angiotensin II Receptor Blocker on Experimental Periodontitis in a Mouse Model of Marfan Syndrome

Structural basis for telmisartan-mediated partial activation of PPAR gamma

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