4ZUD
Crystal Structure of Human Angiotensin Receptor in Complex with Inverse Agonist Olmesartan at 2.8A resolution.
Summary for 4ZUD
| Entry DOI | 10.2210/pdb4zud/pdb |
| Descriptor | Chimera protein of Soluble cytochrome b562 and Type-1 angiotensin II receptor, Olmesartan (2 entities in total) |
| Functional Keywords | 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 |
| Biological source | Escherichia coli More |
| Total number of polymer chains | 1 |
| Total formula weight | 47168.54 |
| Authors | Zhang, H.,Unal, H.,Desnoyer, R.,Han, G.W.,Patel, N.,Katritch, V.,Karnik, S.S.,Cherezov, V.,Stevens, R.C.,GPCR Network (GPCR) (deposition date: 2015-05-15, release date: 2015-10-07, Last modification date: 2024-11-06) |
| Primary citation | 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 Cited by 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: 26420482DOI: 10.1074/jbc.M115.689000 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.8 Å) |
Structure validation
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