4ZUD

Crystal Structure of Human Angiotensin Receptor in Complex with Inverse Agonist Olmesartan at 2.8A resolution.

4ZUD の概要

• エントリーDOI: 10.2210/pdb4zud/pdb
• 分子名称: Chimera protein of Soluble cytochrome b562 and Type-1 angiotensin II receptor, Olmesartan (2 entities in total)
• 機能のキーワード: human angiotensin receptor at1r, bril, g protein-coupled receptor, gpcr, gpcr network, lipidic cubic phase, lcp, membrane protein, structural genomics, olmesartan, angiotensin receptor blocker, anti-hypertensive drug, psi-biology, signaling protein
• 由来する生物種: Escherichia coli; 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 47168.54

構造登録者

Zhang, H.,Unal, H.,Desnoyer, R.,Han, G.W.,Patel, N.,Katritch, V.,Karnik, S.S.,Cherezov, V.,Stevens, R.C.,GPCR Network (GPCR) (登録日: 2015-05-15, 公開日: 2015-10-07, 最終更新日: 2024-11-06)

主引用文献

Zhang, H.,Unal, H.,Desnoyer, R.,Han, G.W.,Patel, N.,Katritch, V.,Karnik, S.S.,Cherezov, V.,Stevens, R.C.
Structural Basis for Ligand Recognition and Functional Selectivity at Angiotensin Receptor.
J.Biol.Chem., 290:29127-29139, 2015

PubMed Abstract: Angiotensin II type 1 receptor (AT1R) is the primary blood pressure regulator. AT1R blockers (ARBs) have been widely used in clinical settings as anti-hypertensive drugs and share a similar chemical scaffold, although even minor variations can lead to distinct therapeutic efficacies toward cardiovascular etiologies. The structural basis for AT1R modulation by different peptide and non-peptide ligands has remained elusive. Here, we report the crystal structure of the human AT1R in complex with an inverse agonist olmesartan (Benicar(TM)), a highly potent anti-hypertensive drug. Olmesartan is anchored to the receptor primarily by the residues Tyr-35(1.39), Trp-84(2.60), and Arg-167(ECL2), similar to the antagonist ZD7155, corroborating a common binding mode of different ARBs. Using docking simulations and site-directed mutagenesis, we identified specific interactions between AT1R and different ARBs, including olmesartan derivatives with inverse agonist, neutral antagonist, or agonist activities. We further observed that the mutation N111(3.35)A in the putative sodium-binding site affects binding of the endogenous peptide agonist angiotensin II but not the β-arrestin-biased peptide TRV120027.

PubMed: 26420482
DOI: 10.1074/jbc.M115.689000

実験手法

X-RAY DIFFRACTION (2.8 Å)