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Identification of Key Residues for Interaction of Vasoactive Intestinal Peptide with Human VPAC1 and VPAC2Receptors and Development of a Highly Selective VPAC1Receptor Agonist
Key parts of a peptide that bind to two human receptors and creation of a peptide that selectively activates one receptor
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Abstract
Substituting residues at 14 positions in vasoactive intestinal peptide (VIP) resulted in a greater than 10-fold increase in binding affinity or biological activity at the VPAC(1) receptor.
- Changes to specific amino acids in VIP were associated with significant alterations in its ability to bind to and activate VPAC(1) and VPAC(2) receptors.
- Substitutions of His(1), Val(5), Arg(14), Lys(15), Lys(21), Leu(23), and Ile(26) reduced the biological activity of VIP without impacting its predicted three-dimensional structure.
- Certain mutations, such as replacing Thr(11) and Asn(28) with alanine, increased binding affinity for the VPAC(2) receptor.
- An alanine substitution at Tyr(22) was linked to an increase in the effectiveness of stimulating adenylyl cyclase activity through the VPAC(2) receptor.
- The combination of mutations at positions 11, 22, and 28 led to the development of a highly selective human VPAC(1) receptor agonist, [Ala(11,22,28)]VIP.
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