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Title: Molecular Recognition of Insulin by a Synthetic Receptor

Abstract

The discovery of molecules that bind tightly and selectively to desired proteins continues to drive innovation at the interface of chemistry and biology. This paper describes the binding of human insulin by the synthetic receptor cucurbit[7]uril (Q7) in vitro. Isothermal titration calorimetry and fluorescence spectroscopy experiments show that Q7 binds to insulin with an equilibrium association constant of 1.5 x 10{sup 6} M{sup -1} and with 50-100-fold selectivity versus proteins that are much larger but lack an N-terminal aromatic residue, and with >1000-fold selectivity versus an insulin variant lacking the N-terminal phenylalanine (Phe) residue. The crystal structure of the Q7{center_dot}insulin complex shows that binding occurs at the N-terminal Phe residue and that the N-terminus unfolds to enable binding. These findings suggest that site-selective recognition is based on the properties inherent to a protein terminus, including the unique chemical epitope presented by the terminal residue and the greater freedom of the terminus to unfold, like the end of a ball of string, to accommodate binding. Insulin recognition was predicted accurately from studies on short peptides and exemplifies an approach to protein recognition by targeting the terminus.

Authors:
; ; ; ; ; ;  [1];  [2]
  1. (Texas-HSC)
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NSFOTHER
OSTI Identifier:
1023665
Resource Type:
Journal Article
Journal Name:
J. Am. Chem. Soc.
Additional Journal Information:
Journal Volume: 133; Journal Issue: (23) ; 06, 2011; Journal ID: ISSN 0002-7863
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; AROMATICS; CALORIMETRY; CHEMISTRY; CRYSTAL STRUCTURE; EQUILIBRIUM; FLUORESCENCE SPECTROSCOPY; HUMAN POPULATIONS; IN VITRO; INSULIN; MOLECULES; PEPTIDES; PHENYLALANINE; PROTEINS; RECEPTORS; RESIDUES; TITRATION

Citation Formats

Chinai, Jordan M., Taylor, Alexander B., Ryno, Lisa M., Hargreaves, Nicholas D., Morris, Christopher A., Hart, P. John, Urbach, Adam R., and Trinity U). Molecular Recognition of Insulin by a Synthetic Receptor. United States: N. p., 2011. Web. doi:10.1021/ja201581x.
Chinai, Jordan M., Taylor, Alexander B., Ryno, Lisa M., Hargreaves, Nicholas D., Morris, Christopher A., Hart, P. John, Urbach, Adam R., & Trinity U). Molecular Recognition of Insulin by a Synthetic Receptor. United States. doi:10.1021/ja201581x.
Chinai, Jordan M., Taylor, Alexander B., Ryno, Lisa M., Hargreaves, Nicholas D., Morris, Christopher A., Hart, P. John, Urbach, Adam R., and Trinity U). Mon . "Molecular Recognition of Insulin by a Synthetic Receptor". United States. doi:10.1021/ja201581x.
@article{osti_1023665,
title = {Molecular Recognition of Insulin by a Synthetic Receptor},
author = {Chinai, Jordan M. and Taylor, Alexander B. and Ryno, Lisa M. and Hargreaves, Nicholas D. and Morris, Christopher A. and Hart, P. John and Urbach, Adam R. and Trinity U)},
abstractNote = {The discovery of molecules that bind tightly and selectively to desired proteins continues to drive innovation at the interface of chemistry and biology. This paper describes the binding of human insulin by the synthetic receptor cucurbit[7]uril (Q7) in vitro. Isothermal titration calorimetry and fluorescence spectroscopy experiments show that Q7 binds to insulin with an equilibrium association constant of 1.5 x 10{sup 6} M{sup -1} and with 50-100-fold selectivity versus proteins that are much larger but lack an N-terminal aromatic residue, and with >1000-fold selectivity versus an insulin variant lacking the N-terminal phenylalanine (Phe) residue. The crystal structure of the Q7{center_dot}insulin complex shows that binding occurs at the N-terminal Phe residue and that the N-terminus unfolds to enable binding. These findings suggest that site-selective recognition is based on the properties inherent to a protein terminus, including the unique chemical epitope presented by the terminal residue and the greater freedom of the terminus to unfold, like the end of a ball of string, to accommodate binding. Insulin recognition was predicted accurately from studies on short peptides and exemplifies an approach to protein recognition by targeting the terminus.},
doi = {10.1021/ja201581x},
journal = {J. Am. Chem. Soc.},
issn = {0002-7863},
number = (23) ; 06, 2011,
volume = 133,
place = {United States},
year = {2011},
month = {8}
}