Elucidation of the Binding Mode of the Carboxyterminal Region of Peptide YY to the Human Y 2 Receptor
Understanding the agonist-receptor interactions in the neuropeptide Y (NPY)/peptide YY (PYY) signaling system is fundamental for the design of novel modulators of appetite regulation. We report here the results of a multidisciplinary approach to elucidate the binding mode of the native peptide agoni...
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Published in | Molecular pharmacology Vol. 93; no. 4; pp. 323 - 334 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
01.04.2018
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Subjects | |
Online Access | Get full text |
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Summary: | Understanding the agonist-receptor interactions in the neuropeptide Y (NPY)/peptide YY (PYY) signaling system is fundamental for the design of novel modulators of appetite regulation. We report here the results of a multidisciplinary approach to elucidate the binding mode of the native peptide agonist PYY to the human Y
receptor, based on computational modeling, peptide chemistry and in vitro pharmacological analyses. The preserved binding orientation proposed for full-length PYY and five analogs, truncated at the amino terminus, explains our pharmacological results where truncations of the N-terminal proline helix showed little effect on peptide affinity. This was followed by receptor mutagenesis to investigate the roles of several receptor positions suggested by the modeling. As a complement, PYY-(3-36) analogs were synthesized with modifications at different positions in the common PYY/NPY C-terminal fragment (
TRQRY
-amide). The results were assessed and interpreted by molecular dynamics and Free Energy Perturbation (FEP) simulations of selected mutants, providing a detailed map of the interactions of the PYY/NPY C-terminal fragment with the transmembrane cavity of the Y
receptor. The amidated C-terminus would be stabilized by polar interactions with Gln288
and Tyr219
, while Gln130
contributes to interactions with Q
in the peptide and T
is close to the tip of TM7 in the receptor. This leaves the core,
-helix of the peptide exposed to make potential interactions with the extracellular loops. This model agrees with most experimental data available for the Y
system and can be used as a basis for optimization of Y
receptor agonists. |
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ISSN: | 0026-895X 1521-0111 1521-0111 |
DOI: | 10.1124/mol.117.110627 |