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We report the molecular recognition properties of Pillar[ n ]MaxQ (P[ n ]MQ) toward a series of (methylated) amino acids, amino acid amides, and post-translationally modified peptides by a combination of 1 H NMR, isothermal titration calorimetry, indicator displacement assays, and molecular dynamics simulations. We find that P6MQ is a potent receptor for N -methylated amino acid side chains. P6MQ recognized the H3K4Me 3 peptide with K d = 16 nM in phosphate buffered saline.
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Conformational investigation of the structure–activity relationship of GdFFD and its analogues on an achatin-like neuropeptide receptor of Aplysia californica involved in the feeding circuit
Proteins and peptides in nature are almost exclusively made from l -amino acids, and this is even more absolute in the metazoan. With the advent of modern bioanalytical techniques, however, previously unappreciated roles for d -amino acids in biological processes have been revealed. Over 30 d -amino acid containing peptides (DAACPs) have been discovered in animals where at least one l -residue has been isomerized to the d -form via an enzyme-catalyzed process. In Aplysia californica , GdFFD and GdYFD (the lower-case letter “d” indicates a d -amino acid residue) modulate the feeding behavior by activating the Aplysia achatin-like neuropeptide receptor (apALNR). However, little is known about how the three-dimensional conformation of DAACPs influences activity at the receptor, and the role that d -residues play in these peptide conformations. Here, we use a combination of computational modeling, drift-tube ion-mobility mass spectrometry, and receptor activation assays to create a simple model that predicts bioactivities for a series of GdFFD analogs. Our results suggest that the active conformations of GdFFD and GdYFD are similar to their lowest energy conformations in solution. Our model helps connect the predicted structures of GdFFD analogs to their activities, and highlights a steric effect on peptide activity at position 1 on the GdFFD receptor apALNR. Overall, these methods allow us to understand ligand–receptor interactions in the absence of high-resolution structural data.
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- Award ID(s):
- 1716956
- PAR ID:
- 10105973
- Date Published:
- Journal Name:
- Physical Chemistry Chemical Physics
- Volume:
- 20
- Issue:
- 34
- ISSN:
- 1463-9076
- Page Range / eLocation ID:
- 22047 to 22057
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/C8CP03661F
