Chemistry & Biology
Volume 1, Issue 4, December 1994, Pages 211-221
Journal home page for Chemistry & Biology

Structural model of antagonist and agonist binding to the angiotensin II, AT1 subtype, G protein coupled receptor

https://doi.org/10.1016/1074-5521(94)90013-2Get rights and content

Abstract

Background: The family of G protein coupled receptors is the largest and perhaps most functionally diverse class of cell-surface receptors. Due to the difficulty of obtaining structural data on membrane proteins there is little information on which to base an understanding of ligand structure-activity relationships, the effects of receptor mutations and the mechanism(s) of signal transduction in this family. We therefore set out to develop a structural model for one such receptor, the human angiotensin II receptor.

Results: An alignment between the human angiotensin II (type 1; hATI), human β2 adrenergic, human neurokinin-1, and human bradykinin receptors, all of which are G protein coupled receptors, was used to generate a three-dimensional model of the hATI receptor based on bacteriorhodopsin. We observed a region within the model that was congruent with the biogenic amine binding site of β2, and were thus able to dock a model of the hAT1 antagonist L-158,282 (MK-996) into the transmembrane region of the receptor model. The antagonist was oriented within the helical domain by recognising that the essential acid functionality of this antagonist interacts with Lys199. The structural model is consistent with much of the information on structure-activity relationships for both non-peptide and peptide ligands.

Conclusions: Our model provides an explanation for the conversion of the antagonist L-158,282 (MK-996) to an agonist by the addition of an isobutyl group. It also suggests a model for domain motion during signal transduction. The approach of independently deriving three-dimensional receptor models and pharmacophore models of the ligands, then combining them, is a powerful technique which helps validate both models.

References (71)

  • Y. Kambayashi et al.

    Molecular cloning of a novel angiotensin II receptor isoform involved in phosphotyrosine phosphatase inhibition.

    J. Biol. Chem.

    (1993)
  • M. Mukoyama et al.

    Expression cloning of type 2 angiotensin II receptor reveals a unique class of seven-transmembrane receptors

    J. Biol. Chem.

    (1993)
  • Y. Yamano et al.

    Identification of amino acid residues of rat angiotensin II receptor for ligand binding by site directed mutagenisis

    Biochem. Biophys. Res. Commun.

    (1992)
  • N.-E. Rhaleb et al.

    Pharmacological characterization of a new highly potent B2 receptor antagonist (HOE 140: dArg-[Hyp3,Thi5, d-Tic7, Oic8]bradykinin)

    Eur. J. Pharmacol.

    (1992)
  • M. Cascieri et al.

    Characterization of the interaction of N-acyl-l-tryptophan benzyl ester neurokinin antagonists with the human Neurokinin-1 receptor

    J. Biol. Chem.

    (1994)
  • T.M. Fong et al.

    The role of histidine-265 in antagonist binding to the Neurokinin-1 receptor

    J. Biol. Chem.

    (1994)
  • T.M. Fong et al.

    Mapping the ligand-binding site of the NK-1 receptor

    Regul. Pept.

    (1993)
  • W. Greenlee et al.

    Angiotensin/renin modulators

    Ann. Rep. Med. Chem.

    (1992)
  • S. Burley et al.

    Amino-aromatic interactions in proteins

    FEBS Letts.

    (1986)
  • S. Burley et al.

    Weakly polar interactions in proteins

    Adv. Protein Chem.

    (1988)
  • M. Levitt et al.

    Aromatic rings act as hydrogen bond acceptors

    J. Mol. Biol.

    (1988)
  • M. Flocco et al.

    Planar stacking interactions of arginine and aromatic side-chains in proteins

    J. Mol. Biol.

    (1994)
  • P. Chakravarty et al.

    Quinazolinone biphenyl acylsulfonamides — a potent new class of angiotensin-II receptor antagonists

    Bioorg. Med. Chem. Letts.

    (1994)
  • T. Nakayama et al.

    Orientation of retinal in bovine rhodopsin determined by cross-linking using photoactivatable analog of 11-cis-retinal

    J. Biol. Chem.

    (1990)
  • T. Nakayama et al.

    Mapping of the amino acids in membrane-embedded helices that interact with the retinal chromophore in bovine rhodopsin

    J. Biol. Chem.

    (1991)
  • D. Banner et al.

    Crystal structure of the soluble human 55KD TNF receptor-human TNF-beta complex: Implications for TNF receptor activation

    Cell

    (1993)
  • R. Maggio et al.

    Reconstitution of functional muscarinic receptors by co-expression of amino and carboxyl terminal receptor fragments

    FEBS Letts.

    (1993)
  • J. Wess

    Molecular basis of muscarinic acetylcholine receptor function

    Trends Pharmacol. Sci.

    (1993)
  • J. Port et al.

    Integration of transmembrane signalling: cross talk among G-protein linked receptors and other signal transduction pathways

    Trends Cardiovasc. Med.

    (1993)
  • G. Milligan

    Mechanisms of multifunctional signalling by G protein linked receptors

    Trends Pharmacol. Sci.

    (1993)
  • E. Taylor et al.

    Sequence homology between bacteriorhodopsin and G-protein coupled receptors: exon shuffling or evolution by duplication?

    FEBS Letts.

    (1993)
  • S. Needleman et al.

    A general method applicable to the search for similarities in the amino acid sequence of two proteins

    J. Mol. Biol.

    (1970)
  • F. Bernstein et al.

    The protein data bank: a computer-based archival file for macromolecular structures

    J. Mol. Biol.

    (1977)
  • G. Schertler et al.

    Projection structure of rhodopsin

    Nature

    (1993)
  • H. de Groot et al.

    Solid-state 13C and 15N NMR study of the low pH forms of bacteriorhodopsin

    Biochemistry

    (1990)
  • Cited by (69)

    • Annotated Bibliography of Dr. Arthur A. Patchett

      2023, Journal of Medicinal Chemistry
    View all citing articles on Scopus
    View full text