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Vol. 279, Issue 1, G126-G131, July 2000

Primary structures of PYY, [Pro³⁴]PYY, and PYY-(3-36) confer different conformations and receptor selectivity

David A. Keire¹, Peter Mannon², Mitsuo Kobayashi¹, John H. Walsh^,3,4, Travis E. Solomon^3,4, and Joseph R. Reeve Jr.^3,4

¹ The Beckman Research Institute of the City of Hope, Duarte, California, 91010-0269; ² Durham Veterans Affairs and Duke University Medical Centers, Durham, North Carolina, 27705; ³ CURE Digestive Diseases Research Center, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles 90073; and ⁴ Digestive Diseases Division, UCLA School of Medicine, Los Angeles, California 90095

We synthesized PYY-(1-36) (nonselective between Y₁ and Y₂ receptor subtype agonists), [Pro³⁴]PYY (selective for Y₁), and PYY-(3-36) (selective for Y₂) to determine whether solution conformation plays a role in receptor subtype selectivity. The three peptides exhibited the expected specificities in displacing labeled PYY-(1-36) from cells transfected with Y₁ receptors (dissociation constants = 0.42, 0.21, and 1,050 nM, respectively) and from cells transfected with Y₂ receptors (dissociation constants = 0.03, 710, and 0.11 nM, respectively) for PYY-(1-36), [Pro³⁴]PYY, and PYY-(3-36). Sedimentation equilibrium analyses revealed that the three PYY analogs were 80-90% monomer at the concentrations used for the subsequent circular dichroism (CD) and ¹H-nuclear magnetic resonance (NMR) studies. CD analysis measured helicities for PYY-(1-36), [Pro³⁴]PYY, and PYY-(3-36) of 42%, 31%, and 24%, suggesting distinct differences in secondary structure. The backbone ¹H-NMR resonances of the three peptides further substantiated marked conformational differences. These patterns support the hypothesis that Y₁ and Y₂ receptor subtype binding affinities depend on the secondary and tertiary solution state structures of PYY and its analogs.

peptide YY; Y₁ receptor; Y₂ receptor; circular dichroism; nuclear magnetic resonance; three-dimensional structure

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 Deceased 14 June 2000.

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