期刊
STRUCTURE
卷 27, 期 3, 页码 537-+出版社
CELL PRESS
DOI: 10.1016/j.str.2018.12.004
关键词
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资金
- EU
- Free State of Saxony [ESF 100148835, 100227414]
- NIH [R01 GM080403, R01 DK097376, R01 HL122010]
- NSF [CHE 1305874]
- Pharmacology Training Grant at Vanderbilt University [T32 GM007628]
The peptide ghrelin targets the growth hormone secretagogue receptor 1a (GHSR) to signal changes in cell metabolism and is a sought-after therapeutic target, although no structure is known to date. To investigate the structural basis of ghrelin binding to GHSR, we used solid-state nuclear magnetic resonance (NMR) spectroscopy, site-directed mutagenesis, and Rosetta modeling. The use of saturation transfer difference NMR identified key residues in the peptide for receptor binding beyond the known motif. This information combined with assignment of the secondary structure of ghrelin in its receptor-bound state was incorporated into Rosetta using an approach that accounts for flexible binding partners. The NMR data and models revealed an extended binding surface that was confirmed via mutagenesis. Our results agree with a growing evidence of peptides interacting via two sites at G protein-coupled receptors.
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