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The paradox of conformational constraint in the design of Cbl(TKB)-binding peptides

Solving the crystal structure of Cbl(TKB) in complex with a pentapeptide, pYTPEP, revealed that the PEP region adopted a poly-L-proline type II (PPII) helix. An unnatural amino acid termed a proline-templated glutamic acid (ptE) that constrained both the backbone and sidechain to the bound conformat...

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Autores principales: Kumar, Eric A., Chen, Qianyi, Kizhake, Smitha, Kolar, Carol, Kang, Myungshim, Chang, Chia-en A., Borgstahl, Gloria E. O., Natarajan, Amarnath
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3965358/
https://www.ncbi.nlm.nih.gov/pubmed/23572190
http://dx.doi.org/10.1038/srep01639
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author Kumar, Eric A.
Chen, Qianyi
Kizhake, Smitha
Kolar, Carol
Kang, Myungshim
Chang, Chia-en A.
Borgstahl, Gloria E. O.
Natarajan, Amarnath
author_facet Kumar, Eric A.
Chen, Qianyi
Kizhake, Smitha
Kolar, Carol
Kang, Myungshim
Chang, Chia-en A.
Borgstahl, Gloria E. O.
Natarajan, Amarnath
author_sort Kumar, Eric A.
collection PubMed
description Solving the crystal structure of Cbl(TKB) in complex with a pentapeptide, pYTPEP, revealed that the PEP region adopted a poly-L-proline type II (PPII) helix. An unnatural amino acid termed a proline-templated glutamic acid (ptE) that constrained both the backbone and sidechain to the bound conformation was synthesized and incorporated into the pYTPXP peptide. We estimated imposing structural constraints onto the backbone and sidechain of the peptide and preorganize it to the bound conformation in solution will yield nearly an order of magnitude improvement in activity. NMR studies confirmed that the ptE-containing peptide adopts the PPII conformation, however, competitive binding studies showed an order of magnitude loss of activity. Given the emphasis that is placed on imposing structural constraints, we provide an example to support the contrary. These results point to conformational flexibility at the interface, which have implications in the design of potent Cbl(TKB)-binding peptides.
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spelling pubmed-39653582014-04-03 The paradox of conformational constraint in the design of Cbl(TKB)-binding peptides Kumar, Eric A. Chen, Qianyi Kizhake, Smitha Kolar, Carol Kang, Myungshim Chang, Chia-en A. Borgstahl, Gloria E. O. Natarajan, Amarnath Sci Rep Article Solving the crystal structure of Cbl(TKB) in complex with a pentapeptide, pYTPEP, revealed that the PEP region adopted a poly-L-proline type II (PPII) helix. An unnatural amino acid termed a proline-templated glutamic acid (ptE) that constrained both the backbone and sidechain to the bound conformation was synthesized and incorporated into the pYTPXP peptide. We estimated imposing structural constraints onto the backbone and sidechain of the peptide and preorganize it to the bound conformation in solution will yield nearly an order of magnitude improvement in activity. NMR studies confirmed that the ptE-containing peptide adopts the PPII conformation, however, competitive binding studies showed an order of magnitude loss of activity. Given the emphasis that is placed on imposing structural constraints, we provide an example to support the contrary. These results point to conformational flexibility at the interface, which have implications in the design of potent Cbl(TKB)-binding peptides. Nature Publishing Group 2013-04-10 /pmc/articles/PMC3965358/ /pubmed/23572190 http://dx.doi.org/10.1038/srep01639 Text en Copyright © 2013, Macmillan Publishers Limited. All rights reserved http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
spellingShingle Article
Kumar, Eric A.
Chen, Qianyi
Kizhake, Smitha
Kolar, Carol
Kang, Myungshim
Chang, Chia-en A.
Borgstahl, Gloria E. O.
Natarajan, Amarnath
The paradox of conformational constraint in the design of Cbl(TKB)-binding peptides
title The paradox of conformational constraint in the design of Cbl(TKB)-binding peptides
title_full The paradox of conformational constraint in the design of Cbl(TKB)-binding peptides
title_fullStr The paradox of conformational constraint in the design of Cbl(TKB)-binding peptides
title_full_unstemmed The paradox of conformational constraint in the design of Cbl(TKB)-binding peptides
title_short The paradox of conformational constraint in the design of Cbl(TKB)-binding peptides
title_sort paradox of conformational constraint in the design of cbl(tkb)-binding peptides
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3965358/
https://www.ncbi.nlm.nih.gov/pubmed/23572190
http://dx.doi.org/10.1038/srep01639
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