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

Eric A. Kumar, Qianyi Chen, Smitha Kizhake, Carol Kolar, Myungshim Kang, Chia En A Chang, Gloria E Borgstahl, Amarnath Natarajan

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number01639
JournalScientific reports
Volume3
DOIs
StatePublished - Apr 10 2013

Fingerprint

Peptides
Competitive Binding
Proline
Glutamic Acid
Amino Acids
polyproline
Peptamen

ASJC Scopus subject areas

  • General

Cite this

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; Natarajan, Amarnath.

In: Scientific reports, Vol. 3, 01639, 10.04.2013.

Research output: Contribution to journalArticle

Kumar, Eric A. ; Chen, Qianyi ; Kizhake, Smitha ; Kolar, Carol ; Kang, Myungshim ; Chang, Chia En A ; Borgstahl, Gloria E ; Natarajan, Amarnath. / The paradox of conformational constraint in the design of Cbl(TKB)-binding peptides. In: Scientific reports. 2013 ; Vol. 3.
@article{e011ec5c9e9241e39829c1ec6241c689,
title = "The paradox of conformational constraint in the design of Cbl(TKB)-binding peptides",
abstract = "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.",
author = "Kumar, {Eric A.} and Qianyi Chen and Smitha Kizhake and Carol Kolar and Myungshim Kang and Chang, {Chia En A} and Borgstahl, {Gloria E} and Amarnath Natarajan",
year = "2013",
month = "4",
day = "10",
doi = "10.1038/srep01639",
language = "English (US)",
volume = "3",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - The paradox of conformational constraint in the design of Cbl(TKB)-binding peptides

AU - Kumar, Eric A.

AU - Chen, Qianyi

AU - Kizhake, Smitha

AU - Kolar, Carol

AU - Kang, Myungshim

AU - Chang, Chia En A

AU - Borgstahl, Gloria E

AU - Natarajan, Amarnath

PY - 2013/4/10

Y1 - 2013/4/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84902940152&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84902940152&partnerID=8YFLogxK

U2 - 10.1038/srep01639

DO - 10.1038/srep01639

M3 - Article

C2 - 23572190

AN - SCOPUS:84902940152

VL - 3

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 01639

ER -