TY - JOUR
T1 - Conformational investigation of the structure-activity relationship of GdFFD and its analogues on an achatin-like neuropeptide receptor of
T2 - Aplysia californica involved in the feeding circuit
AU - Do, Thanh D.
AU - Checco, James W.
AU - Tro, Michael
AU - Shea, Joan Emma
AU - Bowers, Michael T.
AU - Sweedler, Jonathan V.
N1 - Publisher Copyright:
© 2018 the Owner Societies.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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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U2 - 10.1039/c8cp03661f
DO - 10.1039/c8cp03661f
M3 - Article
C2 - 30112548
AN - SCOPUS:85052846538
SN - 1463-9076
VL - 20
SP - 22047
EP - 22057
JO - Physical Chemistry Chemical Physics
JF - Physical Chemistry Chemical Physics
IS - 34
ER -