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Natural and non-natural amino-acid side-chain substitutions: affinity and diffraction studies of meditope–Fab complexes
Herein, multiple crystal structures of meditope peptide derivatives incorporating natural and unnatural amino acids bound to the cetuximab Fab domain are presented. The affinity of each derivative was determined by surface plasmon resonance and correlated to the atomic structure. Overall, it was obs...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
International Union of Crystallography
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5101583/ https://www.ncbi.nlm.nih.gov/pubmed/27834791 http://dx.doi.org/10.1107/S2053230X16016149 |
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author | Bzymek, Krzysztof P. Avery, Kendra A. Ma, Yuelong Horne, David A. Williams, John C. |
author_facet | Bzymek, Krzysztof P. Avery, Kendra A. Ma, Yuelong Horne, David A. Williams, John C. |
author_sort | Bzymek, Krzysztof P. |
collection | PubMed |
description | Herein, multiple crystal structures of meditope peptide derivatives incorporating natural and unnatural amino acids bound to the cetuximab Fab domain are presented. The affinity of each derivative was determined by surface plasmon resonance and correlated to the atomic structure. Overall, it was observed that the hydrophobic residues in the meditope peptide, Phe3, Leu5 and Leu10, could accommodate a number of moderate substitutions, but these invariably reduced the overall affinity and half-life of the interaction. In one case, the substitution of Phe3 by histidine led to a change in the rotamer conformation, in which the imidazole ring flipped to a solvent-exposed position. Based on this observation, Phe3 was substituted by diphenylalanine and it was found that the phenyl rings in this variant mimic the superposition of the Phe3 and His3 structures, producing a moderate increase, of 1.4-fold, in the half-life of the complex. In addition, it was observed that substitution of Leu5 by tyrosine and glutamate strongly reduced the affinity, whereas the substitution of Leu5 by diphenylalanine moderately reduced the half-life (by approximately fivefold). Finally, it was observed that substitution of Arg8 and Arg9 by citrulline dramatically reduced the overall affinity, presumably owing to lost electrostatic interactions. Taken together, these studies provide insight into the meditope–cetuximab interaction at the atomic level. |
format | Online Article Text |
id | pubmed-5101583 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | International Union of Crystallography |
record_format | MEDLINE/PubMed |
spelling | pubmed-51015832016-11-11 Natural and non-natural amino-acid side-chain substitutions: affinity and diffraction studies of meditope–Fab complexes Bzymek, Krzysztof P. Avery, Kendra A. Ma, Yuelong Horne, David A. Williams, John C. Acta Crystallogr F Struct Biol Commun Research Communications Herein, multiple crystal structures of meditope peptide derivatives incorporating natural and unnatural amino acids bound to the cetuximab Fab domain are presented. The affinity of each derivative was determined by surface plasmon resonance and correlated to the atomic structure. Overall, it was observed that the hydrophobic residues in the meditope peptide, Phe3, Leu5 and Leu10, could accommodate a number of moderate substitutions, but these invariably reduced the overall affinity and half-life of the interaction. In one case, the substitution of Phe3 by histidine led to a change in the rotamer conformation, in which the imidazole ring flipped to a solvent-exposed position. Based on this observation, Phe3 was substituted by diphenylalanine and it was found that the phenyl rings in this variant mimic the superposition of the Phe3 and His3 structures, producing a moderate increase, of 1.4-fold, in the half-life of the complex. In addition, it was observed that substitution of Leu5 by tyrosine and glutamate strongly reduced the affinity, whereas the substitution of Leu5 by diphenylalanine moderately reduced the half-life (by approximately fivefold). Finally, it was observed that substitution of Arg8 and Arg9 by citrulline dramatically reduced the overall affinity, presumably owing to lost electrostatic interactions. Taken together, these studies provide insight into the meditope–cetuximab interaction at the atomic level. International Union of Crystallography 2016-10-24 /pmc/articles/PMC5101583/ /pubmed/27834791 http://dx.doi.org/10.1107/S2053230X16016149 Text en © Bzymek et al. 2016 http://creativecommons.org/licenses/by/2.0/uk/ This is an open-access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited. |
spellingShingle | Research Communications Bzymek, Krzysztof P. Avery, Kendra A. Ma, Yuelong Horne, David A. Williams, John C. Natural and non-natural amino-acid side-chain substitutions: affinity and diffraction studies of meditope–Fab complexes |
title | Natural and non-natural amino-acid side-chain substitutions: affinity and diffraction studies of meditope–Fab complexes |
title_full | Natural and non-natural amino-acid side-chain substitutions: affinity and diffraction studies of meditope–Fab complexes |
title_fullStr | Natural and non-natural amino-acid side-chain substitutions: affinity and diffraction studies of meditope–Fab complexes |
title_full_unstemmed | Natural and non-natural amino-acid side-chain substitutions: affinity and diffraction studies of meditope–Fab complexes |
title_short | Natural and non-natural amino-acid side-chain substitutions: affinity and diffraction studies of meditope–Fab complexes |
title_sort | natural and non-natural amino-acid side-chain substitutions: affinity and diffraction studies of meditope–fab complexes |
topic | Research Communications |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5101583/ https://www.ncbi.nlm.nih.gov/pubmed/27834791 http://dx.doi.org/10.1107/S2053230X16016149 |
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