期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 16, 期 20, 页码 9359-9368出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2008.08.051
关键词
neurotensin receptor; neuropeptide receptor interactions; molecular modeling; extracellular loop 1; radioligand binding; site-directed mutagenesis; peptide backbone modifications
资金
- Deutsche Forschungsgemeinschaft [Gm13/7]
Investigating prototypical interactions between NT(8-13) and the human neurotensin receptor 1 (hNTR1), we created a receptor-ligand model that was validated by site-directed mutagenesis and structure-activity relationship studies. Stabilization of the extracellular loop 1 (EL1) by pi-stacking clusters proved to be important for agonist binding when substitution of six conserved amino acids by alanine resulted in an agonist specific loss of maximal binding capacity. In agreement with our modeling studies, EL1 seems to adopt a clamp-type border area controlling the shape of the binding site crevice. Employing chemically manipulated peptide analogs as molecular probes, the impact of backbone modi. cations on receptor-ligand interaction, especially the influence on ligand conformation, was examined in binding studies and explained by in silico analysis. (c) 2008 Elsevier Ltd. All rights reserved.
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