The structure of bioactive analogs of the N-terminal region of gastrin-17

Jeffrey Copps, Richard F. Murphy, Sándor Lovas

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Gastrin-17 (G17) processing intermediates bind to non-CCK receptors which mediate growth of the colonic mucosa but also the formation and development of colonic cancers. In previous studies, we removed the C-terminal region of G17 to form G17(1-12) and considerably shorter C-terminally amidated and non-amidated analogs. Peptides as short as G17(1-4) continued to bind to a single site on DLD-1 human colonic carcinoma cells, while only the G17(1-6)-NH2 and G17(1-12) peptides retained the ability to activate the receptor and stimulate cell proliferation in vitro. In this report, we studied the structure of these analogs, using a combination of ECD and VCD spectroscopy and replica exchange molecular dynamics (REMD) simulations in water, TFE, and membrane-mimicking environments, in order to determine preferred conformations that may have importance in promoting the biological activities. Mostly random meander structures, punctuated by a β-turn at residues 1-4, were found in most peptides by REMD simulations. G17(1-3)-NH2, which cannot form a β-turn, failed to bind the non-CCK receptor, suggesting the importance of this feature for binding. Additionally, the β-turn appeared more frequently in longer sequences, possibly explaining the higher affinity of the non-CCK receptor for these peptides seen previously. Finally, C-terminally amidated peptides generally showed greater formation of turn structure than their non-amidated counterparts as shown by ECD spectra, suggesting the importance of peptide length in stabilizing turn structure in N-terminal sequences, and perhaps explaining the ability of G17(1-6)-NH2 to activate the non-CCK receptor where as the non-amidated G17(1-6) and shorter peptides do not.

Original languageEnglish
Pages (from-to)2250-2262
Number of pages13
JournalPeptides
Volume30
Issue number12
DOIs
StatePublished - Dec 2009

Fingerprint

Peptides
Molecular Dynamics Simulation
Molecular dynamics
gastrin 17
Peptide Receptors
Computer simulation
Cell proliferation
Polytetrafluoroethylene
Bioactivity
Colonic Neoplasms
Conformations
Spectrum Analysis
Mucous Membrane
Cells
Cell Proliferation
Spectroscopy
Membranes
Carcinoma
Water
Growth

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Endocrinology
  • Physiology
  • Cellular and Molecular Neuroscience

Cite this

The structure of bioactive analogs of the N-terminal region of gastrin-17. / Copps, Jeffrey; Murphy, Richard F.; Lovas, Sándor.

In: Peptides, Vol. 30, No. 12, 12.2009, p. 2250-2262.

Research output: Contribution to journalArticle

Copps, Jeffrey ; Murphy, Richard F. ; Lovas, Sándor. / The structure of bioactive analogs of the N-terminal region of gastrin-17. In: Peptides. 2009 ; Vol. 30, No. 12. pp. 2250-2262.
@article{0a1291ae06824b8099ab85700a56b30c,
title = "The structure of bioactive analogs of the N-terminal region of gastrin-17",
abstract = "Gastrin-17 (G17) processing intermediates bind to non-CCK receptors which mediate growth of the colonic mucosa but also the formation and development of colonic cancers. In previous studies, we removed the C-terminal region of G17 to form G17(1-12) and considerably shorter C-terminally amidated and non-amidated analogs. Peptides as short as G17(1-4) continued to bind to a single site on DLD-1 human colonic carcinoma cells, while only the G17(1-6)-NH2 and G17(1-12) peptides retained the ability to activate the receptor and stimulate cell proliferation in vitro. In this report, we studied the structure of these analogs, using a combination of ECD and VCD spectroscopy and replica exchange molecular dynamics (REMD) simulations in water, TFE, and membrane-mimicking environments, in order to determine preferred conformations that may have importance in promoting the biological activities. Mostly random meander structures, punctuated by a β-turn at residues 1-4, were found in most peptides by REMD simulations. G17(1-3)-NH2, which cannot form a β-turn, failed to bind the non-CCK receptor, suggesting the importance of this feature for binding. Additionally, the β-turn appeared more frequently in longer sequences, possibly explaining the higher affinity of the non-CCK receptor for these peptides seen previously. Finally, C-terminally amidated peptides generally showed greater formation of turn structure than their non-amidated counterparts as shown by ECD spectra, suggesting the importance of peptide length in stabilizing turn structure in N-terminal sequences, and perhaps explaining the ability of G17(1-6)-NH2 to activate the non-CCK receptor where as the non-amidated G17(1-6) and shorter peptides do not.",
author = "Jeffrey Copps and Murphy, {Richard F.} and S{\'a}ndor Lovas",
year = "2009",
month = "12",
doi = "10.1016/j.peptides.2009.09.016",
language = "English",
volume = "30",
pages = "2250--2262",
journal = "Peptides",
issn = "0196-9781",
publisher = "Elsevier Inc.",
number = "12",

}

TY - JOUR

T1 - The structure of bioactive analogs of the N-terminal region of gastrin-17

AU - Copps, Jeffrey

AU - Murphy, Richard F.

AU - Lovas, Sándor

PY - 2009/12

Y1 - 2009/12

N2 - Gastrin-17 (G17) processing intermediates bind to non-CCK receptors which mediate growth of the colonic mucosa but also the formation and development of colonic cancers. In previous studies, we removed the C-terminal region of G17 to form G17(1-12) and considerably shorter C-terminally amidated and non-amidated analogs. Peptides as short as G17(1-4) continued to bind to a single site on DLD-1 human colonic carcinoma cells, while only the G17(1-6)-NH2 and G17(1-12) peptides retained the ability to activate the receptor and stimulate cell proliferation in vitro. In this report, we studied the structure of these analogs, using a combination of ECD and VCD spectroscopy and replica exchange molecular dynamics (REMD) simulations in water, TFE, and membrane-mimicking environments, in order to determine preferred conformations that may have importance in promoting the biological activities. Mostly random meander structures, punctuated by a β-turn at residues 1-4, were found in most peptides by REMD simulations. G17(1-3)-NH2, which cannot form a β-turn, failed to bind the non-CCK receptor, suggesting the importance of this feature for binding. Additionally, the β-turn appeared more frequently in longer sequences, possibly explaining the higher affinity of the non-CCK receptor for these peptides seen previously. Finally, C-terminally amidated peptides generally showed greater formation of turn structure than their non-amidated counterparts as shown by ECD spectra, suggesting the importance of peptide length in stabilizing turn structure in N-terminal sequences, and perhaps explaining the ability of G17(1-6)-NH2 to activate the non-CCK receptor where as the non-amidated G17(1-6) and shorter peptides do not.

AB - Gastrin-17 (G17) processing intermediates bind to non-CCK receptors which mediate growth of the colonic mucosa but also the formation and development of colonic cancers. In previous studies, we removed the C-terminal region of G17 to form G17(1-12) and considerably shorter C-terminally amidated and non-amidated analogs. Peptides as short as G17(1-4) continued to bind to a single site on DLD-1 human colonic carcinoma cells, while only the G17(1-6)-NH2 and G17(1-12) peptides retained the ability to activate the receptor and stimulate cell proliferation in vitro. In this report, we studied the structure of these analogs, using a combination of ECD and VCD spectroscopy and replica exchange molecular dynamics (REMD) simulations in water, TFE, and membrane-mimicking environments, in order to determine preferred conformations that may have importance in promoting the biological activities. Mostly random meander structures, punctuated by a β-turn at residues 1-4, were found in most peptides by REMD simulations. G17(1-3)-NH2, which cannot form a β-turn, failed to bind the non-CCK receptor, suggesting the importance of this feature for binding. Additionally, the β-turn appeared more frequently in longer sequences, possibly explaining the higher affinity of the non-CCK receptor for these peptides seen previously. Finally, C-terminally amidated peptides generally showed greater formation of turn structure than their non-amidated counterparts as shown by ECD spectra, suggesting the importance of peptide length in stabilizing turn structure in N-terminal sequences, and perhaps explaining the ability of G17(1-6)-NH2 to activate the non-CCK receptor where as the non-amidated G17(1-6) and shorter peptides do not.

UR - http://www.scopus.com/inward/record.url?scp=70449670331&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70449670331&partnerID=8YFLogxK

U2 - 10.1016/j.peptides.2009.09.016

DO - 10.1016/j.peptides.2009.09.016

M3 - Article

VL - 30

SP - 2250

EP - 2262

JO - Peptides

JF - Peptides

SN - 0196-9781

IS - 12

ER -