Primary structures of PYY, [Pro(34)]PYY, and PYY-(3-36) confer different conformations and receptor selectivity
D A Keire1, P Mannon, M Kobayashi
1The Beckman Research Institute of the City of Hope, Duarte, California 91010-0269, USA.
Summary
Solution conformation influences peptide receptor selectivity. Different secondary structures of PYY analogs correlate with distinct Y(1) and Y(2) receptor binding affinities, impacting drug development.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Peptide hormones like PYY (Peptide YY) interact with specific receptor subtypes.
- Understanding receptor subtype selectivity is crucial for developing targeted therapeutics.
- The role of peptide conformation in receptor binding specificity requires further investigation.
Purpose of the Study:
- To investigate whether the solution conformation of PYY (Peptide YY) analogs affects their selectivity for Y(1) and Y(2) receptor subtypes.
- To correlate structural differences with binding affinities at Y(1) and Y(2) receptors.
Main Methods:
- Synthesis of three PYY analogs: PYY-(1-36), [Pro(34)]PYY, and PYY-(3-36).
- Receptor binding assays using cells transfected with Y(1) and Y(2) receptors to determine dissociation constants.
- Sedimentation equilibrium analysis to assess peptide monomer concentration.
- Circular dichroism (CD) spectroscopy to measure secondary structure content (helicities).
- (1)H-nuclear magnetic resonance ((1)H-NMR) spectroscopy to analyze backbone conformational differences.
Main Results:
- The synthesized PYY analogs demonstrated expected receptor subtype specificities.
- PYY-(1-36), [Pro(34)]PYY, and PYY-(3-36) showed distinct binding affinities for Y(1) and Y(2) receptors.
- CD and (1)H-NMR analyses revealed significant differences in the secondary and tertiary structures of the PYY analogs in solution.
- Peptides existed primarily as monomers at the concentrations used in structural studies.
Conclusions:
- Solution conformation, including secondary and tertiary structures, plays a significant role in determining the binding affinities of PYY analogs to Y(1) and Y(2) receptor subtypes.
- These findings support the hypothesis that structural states dictate receptor subtype selectivity for PYY and its derivatives.
- Understanding these structure-activity relationships can inform the design of more selective peptide-based drugs.
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