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Exploring Non‐obvious Hydrophobic Binding Pockets on Protein Surfaces: Increasing Affinities in Peptide–Protein Interactions
Author(s) -
Balliu Aleksandra,
Baltzer Lars
Publication year - 2017
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201700048
Subject(s) - chemistry , affinities , peptide , binding affinities , residue (chemistry) , conjugate , amino acid , conjugated system , stereochemistry , biochemistry , receptor , organic chemistry , polymer , mathematical analysis , mathematics
A 42‐residue polypeptide conjugated to a small‐molecule organic ligand capable of targeting the phosphorylated side chain of Ser15 was shown to bind glycogen phosphorylase a (GPa) with a K D value of 280 n m . The replacement of hydrophobic amino acids by Ala reduced affinities, whereas the incorporation of l ‐2‐aminooctanoic acid (Aoc) increased them. Replacing Nle5, Ile9 and Leu12 by Aoc reduced the K D value from 280 to 27 n m . “Downsizing” the 42‐mer to an undecamer gave rise to an affinity for GPa an order of magnitude lower, but the undecamer in which Nle5, Ile9 and Leu12 were replaced by Aoc showed a K D value of 550 n m , comparable with that of the parent 42‐mer. The use of Aoc residues offers a convenient route to increased affinity in protein recognition as well as a strategy for the “downsizing” of peptides essentially without loss of affinity. The results show that hydrophobic binding sites can be found on protein surfaces by comparing the affinities of polypeptide conjugates in which Aoc residues replace Nle, Ile, Leu or Phe with those of their unmodified counterparts. Polypeptide conjugates thus provide valuable opportunities for the optimization of peptides and small organic compounds in biotechnology and biomedicine.