A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Three-dimensional models of alpha(2A)-adrenergic receptor complexes provide a structural explanation for ligand binding
Tekijät: Salminen T, Varis M, Nyronen T, Pihlavisto M, Hoffren AM, Lonnberg T, Marjamaki A, Frang H, Savola JM, Scheinin M, Johnson MS
Kustantaja: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Julkaisuvuosi: 1999
Lehti:: Journal of Biological Chemistry
Tietokannassa oleva lehden nimi: JOURNAL OF BIOLOGICAL CHEMISTRY
Lehden akronyymi: J BIOL CHEM
Vuosikerta: 274
Numero: 33
Aloitussivu: 23405
Lopetussivu: 23413
Sivujen määrä: 9
ISSN: 0021-9258
DOI: https://doi.org/10.1074/jbc.274.33.23405
Tiivistelmä
We have compared bacteriorhodopsin-based (alpha(2A)-AR(BR)) and rhodopsin-based (alpha(2A)-AR(R)) models of the human alpha(2A)-adrenengic receptor (alpha(2A)-AR) using both docking simulations and experimental receptor alkylation studies with chloroethylclonidine and a-aminoethyl methanethiosulfonate hydrobromide. The results indicate that the alpha(2A)-AR(R) model provides a better explanation for ligand binding than does our alpha(2A)-AR(BR) model. Thus, we have made an extensive analysis of ligand binding to alpha(2A)-AR(R) and engineered mutant receptors using clonidine, para-aminoclonidine, oxymetazoline, 5-bromo-N-(4, 5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK14,304), and norepinephrine as ligands, The representative docked ligand conformation was chosen using extensive docking simulations coupled with the identification of favorable interaction sites for chemical groups in the receptor, These ligand-protein complex studies provide a rational explanation at the atomic level for the experimentally observed binding affinities of each of these ligands to the alpha(2A)-adrenergic receptor.
We have compared bacteriorhodopsin-based (alpha(2A)-AR(BR)) and rhodopsin-based (alpha(2A)-AR(R)) models of the human alpha(2A)-adrenengic receptor (alpha(2A)-AR) using both docking simulations and experimental receptor alkylation studies with chloroethylclonidine and a-aminoethyl methanethiosulfonate hydrobromide. The results indicate that the alpha(2A)-AR(R) model provides a better explanation for ligand binding than does our alpha(2A)-AR(BR) model. Thus, we have made an extensive analysis of ligand binding to alpha(2A)-AR(R) and engineered mutant receptors using clonidine, para-aminoclonidine, oxymetazoline, 5-bromo-N-(4, 5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK14,304), and norepinephrine as ligands, The representative docked ligand conformation was chosen using extensive docking simulations coupled with the identification of favorable interaction sites for chemical groups in the receptor, These ligand-protein complex studies provide a rational explanation at the atomic level for the experimentally observed binding affinities of each of these ligands to the alpha(2A)-adrenergic receptor.
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