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PDBsum entry 4zud
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Membrane protein
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PDB id
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4zud
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References listed in PDB file
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Key reference
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Title
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Structural basis for ligand recognition and functional selectivity at angiotensin receptor.
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Authors
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H.Zhang,
H.Unal,
R.Desnoyer,
G.W.Han,
N.Patel,
V.Katritch,
S.S.Karnik,
V.Cherezov,
R.C.Stevens.
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Ref.
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J Biol Chem, 2015,
290,
29127-29139.
[DOI no: ]
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PubMed id
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Note: In the PDB file this reference is
annotated as "TO BE PUBLISHED". The citation details given above have
been manually determined.
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Abstract
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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.
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