4ZUD

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


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.196 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

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

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

(2015) J Biol Chem 290: 29127-29139

  • DOI: https://doi.org/10.1074/jbc.M115.689000
  • Primary Citation of Related Structures:  
    4ZUD

  • 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.


  • Organizational Affiliation

    From the Departments of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089 and.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Chimera protein of Soluble cytochrome b562 and Type-1 angiotensin II receptor410Escherichia coliHomo sapiensMutation(s): 3 
Gene Names: cybCAGTR1AGTR1AAGTR1BAT2R1AT2R1B
Membrane Entity: Yes 
UniProt & NIH Common Fund Data Resources
Find proteins for P30556 (Homo sapiens)
Explore P30556 
Go to UniProtKB:  P30556
PHAROS:  P30556
GTEx:  ENSG00000144891 
Find proteins for P0ABE7 (Escherichia coli)
Explore P0ABE7 
Go to UniProtKB:  P0ABE7
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupsP0ABE7P30556
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
OLM
Query on OLM

Download Ideal Coordinates CCD File 
B [auth A]Olmesartan
C24 H26 N6 O3
VTRAEEWXHOVJFV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
OLM BindingDB:  4ZUD IC50: min: 7.7, max: 8.1 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.196 
  • Space Group: P 32
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.2α = 90
b = 41.2β = 90
c = 251.16γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesU54 GM094618

Revision History  (Full details and data files)

  • Version 1.0: 2015-10-07
    Type: Initial release
  • Version 1.1: 2015-10-14
    Changes: Database references
  • Version 1.2: 2015-12-16
    Changes: Database references
  • Version 1.3: 2017-09-20
    Changes: Author supporting evidence, Database references, Derived calculations
  • Version 1.4: 2019-12-25
    Changes: Author supporting evidence
  • Version 1.5: 2023-09-27
    Changes: Data collection, Database references, Refinement description