PDBsum entry 4zud

Membrane protein

PDB id: 4zud

Contents

Protein chain

376 a.a.

Ligands

OLM

PDB id:

4zud

Name:

Membrane protein

Title:

Crystal structure of human angiotensin receptor in complex with inverse agonist olmesartan at 2.8a resolution.

Structure:

Chimera protein of soluble cytochrome b562 and type-1 angiotensin ii receptor. Chain: a. Synonym: cytochrome b-562,at1ar,at1br,angiotensin ii type-1 receptor, at1,at1ar,at1br,angiotensin ii type-1 receptor,at1. Engineered: yes. Mutation: yes

Source:

Escherichia coli, homo sapiens. Human. Organism_taxid: 562, 9606. Gene: cybc, agtr1, agtr1a, agtr1b, at2r1, at2r1b. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9. Expression_system_atcc_number: crl-1711.

Resolution:

2.80Å R-factor: 0.196 R-free: 0.235

Authors:

H.Zhang,H.Unal,R.Desnoyer,G.W.Han,N.Patel,V.Katritch,S.S.Karnik, V.Cherezov,R.C.Stevens,Gpcr Network (Gpcr)

Key ref:

H.Zhang et al. (2015). Structural Basis for Ligand Recognition and Functional Selectivity at Angiotensin Receptor. J Biol Chem, 290, 29127-29139. PubMed id: 26420482 DOI: 10.1074/jbc.M115.689000

Date:

15-May-15 Release date: 07-Oct-15

Protein chain

P0ABE7  (C562_ECOLX) -  Soluble cytochrome b562 from Escherichia coli

Seq: 128 a.a.

Struc: 376 a.a.*

Protein chain

P30556  (AGTR1_HUMAN) -  Type-1 angiotensin II receptor from Homo sapiens

Seq: 359 a.a.

Struc: 376 a.a.*

* PDB and UniProt seqs differ at 18 residue positions (black crosses)

DOI no: 10.1074/jbc.M115.689000

J Biol Chem 290:29127-29139 (2015)

PubMed id: 26420482

Structural Basis for Ligand Recognition and Functional Selectivity at Angiotensin Receptor.

H.Zhang, H.Unal, R.Desnoyer, G.W.Han, N.Patel, V.Katritch, S.S.Karnik, V.Cherezov, R.C.Stevens.

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.