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Title: Folding Then Binding vs Folding Through Binding in Macrocyclic Peptide Inhibitors of Human Pancreatic α-Amylase

Abstract

De novo macrocyclic peptides, derived using selection technologies such as phage and mRNA display, present unique and unexpected solutions to challenging biological problems. This is due in part to their unusual folds, which are able to present side chains in ways not available to canonical structures such as α-helices and β-sheets. Despite much recent interest in these molecules, their folding and binding behavior remains poorly characterized. In this work, we present cocrystallization, docking, and solution NMR structures of three de novo macrocyclic peptides that all bind as competitive inhibitors with single-digit nanomolar Ki to the active site of human pancreatic α-amylase. We show that a short stably folded motif in one of these is nucleated by internal hydrophobic interactions in an otherwise dynamic conformation in solution. Comparison of the solution structures with a target-bound structure from docking indicates that stabilization of the bound conformation is provided through interactions with the target protein after binding. These three structures also reveal a surprising functional convergence to present a motif of a single arginine sandwiched between two aromatic residues in the interactions of the peptide with the key catalytic residues of the enzyme, despite little to no other structural homology. Our results suggestmore » that intramolecular hydrophobic interactions are important for priming binding of small macrocyclic peptides to their target and that high rigidity is not necessary for high affinity.« less

Authors:
 [1]; ORCiD logo [1];  [2];  [1];  [2];  [1];  [1];  [1];  [1];  [2]; ORCiD logo [1]; ORCiD logo [1]
  1. Utrecht Univ., Utrecht (The Netherlands)
  2. Univ. of British Columbia, Vancouver, BC (Canada)
Publication Date:
Research Org.:
Utrecht Univ., Utrecht (The Netherlands)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1557693
Grant/Contract Number:  
AC02-76SF00515
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
ACS Chemical Biology
Additional Journal Information:
Journal Volume: 14; Journal Issue: 8; Journal ID: ISSN 1554-8929
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Goldbach, Leander, Vermeulen, Bram J. A., Caner, Sami, Liu, Minglong, Tysoe, Christina, van Gijzel, Lieke, Yoshisada, Ryoji, Trellet, Mikael, van Ingen, Hugo, Brayer, Gary D., Bonvin, Alexandre M. J. J., and Jongkees, Seino A. K. Folding Then Binding vs Folding Through Binding in Macrocyclic Peptide Inhibitors of Human Pancreatic α-Amylase. United States: N. p., 2019. Web. doi:10.1021/acschembio.9b00290.
Goldbach, Leander, Vermeulen, Bram J. A., Caner, Sami, Liu, Minglong, Tysoe, Christina, van Gijzel, Lieke, Yoshisada, Ryoji, Trellet, Mikael, van Ingen, Hugo, Brayer, Gary D., Bonvin, Alexandre M. J. J., & Jongkees, Seino A. K. Folding Then Binding vs Folding Through Binding in Macrocyclic Peptide Inhibitors of Human Pancreatic α-Amylase. United States. https://doi.org/10.1021/acschembio.9b00290
Goldbach, Leander, Vermeulen, Bram J. A., Caner, Sami, Liu, Minglong, Tysoe, Christina, van Gijzel, Lieke, Yoshisada, Ryoji, Trellet, Mikael, van Ingen, Hugo, Brayer, Gary D., Bonvin, Alexandre M. J. J., and Jongkees, Seino A. K. Wed . "Folding Then Binding vs Folding Through Binding in Macrocyclic Peptide Inhibitors of Human Pancreatic α-Amylase". United States. https://doi.org/10.1021/acschembio.9b00290. https://www.osti.gov/servlets/purl/1557693.
@article{osti_1557693,
title = {Folding Then Binding vs Folding Through Binding in Macrocyclic Peptide Inhibitors of Human Pancreatic α-Amylase},
author = {Goldbach, Leander and Vermeulen, Bram J. A. and Caner, Sami and Liu, Minglong and Tysoe, Christina and van Gijzel, Lieke and Yoshisada, Ryoji and Trellet, Mikael and van Ingen, Hugo and Brayer, Gary D. and Bonvin, Alexandre M. J. J. and Jongkees, Seino A. K.},
abstractNote = {De novo macrocyclic peptides, derived using selection technologies such as phage and mRNA display, present unique and unexpected solutions to challenging biological problems. This is due in part to their unusual folds, which are able to present side chains in ways not available to canonical structures such as α-helices and β-sheets. Despite much recent interest in these molecules, their folding and binding behavior remains poorly characterized. In this work, we present cocrystallization, docking, and solution NMR structures of three de novo macrocyclic peptides that all bind as competitive inhibitors with single-digit nanomolar Ki to the active site of human pancreatic α-amylase. We show that a short stably folded motif in one of these is nucleated by internal hydrophobic interactions in an otherwise dynamic conformation in solution. Comparison of the solution structures with a target-bound structure from docking indicates that stabilization of the bound conformation is provided through interactions with the target protein after binding. These three structures also reveal a surprising functional convergence to present a motif of a single arginine sandwiched between two aromatic residues in the interactions of the peptide with the key catalytic residues of the enzyme, despite little to no other structural homology. Our results suggest that intramolecular hydrophobic interactions are important for priming binding of small macrocyclic peptides to their target and that high rigidity is not necessary for high affinity.},
doi = {10.1021/acschembio.9b00290},
url = {https://www.osti.gov/biblio/1557693}, journal = {ACS Chemical Biology},
issn = {1554-8929},
number = 8,
volume = 14,
place = {United States},
year = {2019},
month = {6}
}

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