Characterization of binding mode of imatinib to human α 1-acid glycoprotein

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5 Citations (Scopus)

Abstract

Imatinib (IMT) is a selective tyrosine kinase inhibitor, used in the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Its strong plasma protein binding was found to belong to the F1*S genetic variant of α 1-acid glycoprotein (AGP). In this work, comparative AGP binding studies were performed with IMT fragment molecules to reveal which parts of the molecule are important in the high-affinity interaction provoking specific spectral changes. Molecular modeling calculations indicated that IMT docked into the X-ray structure of AGP/F1 adopts a bent, compact conformation. This binding mode is similar to those found in its complexes with some low-affinity kinases and a quinone reductase, being strikingly different from the extended conformation of IMT in its high-affinity kinase targets.

Original languageEnglish
Pages (from-to)788-795
Number of pages8
JournalInternational Journal of Biological Macromolecules
Volume50
Issue number3
DOIs
Publication statusPublished - Apr 1 2012

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Glycoproteins
Acids
Conformations
Phosphotransferases
NAD(P)H Dehydrogenase (Quinone)
Gastrointestinal Stromal Tumors
Molecules
Molecular modeling
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Protein Binding
Protein-Tyrosine Kinases
Blood Proteins
Tumors
X-Rays
X rays
Imatinib Mesylate

Keywords

  • α -Acid glycoprotein
  • Fluorescence quenching
  • Genetic variants
  • Imatinib
  • Induced circular dichroism
  • Protein binding

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Cite this

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title = "Characterization of binding mode of imatinib to human α 1-acid glycoprotein",
abstract = "Imatinib (IMT) is a selective tyrosine kinase inhibitor, used in the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Its strong plasma protein binding was found to belong to the F1*S genetic variant of α 1-acid glycoprotein (AGP). In this work, comparative AGP binding studies were performed with IMT fragment molecules to reveal which parts of the molecule are important in the high-affinity interaction provoking specific spectral changes. Molecular modeling calculations indicated that IMT docked into the X-ray structure of AGP/F1 adopts a bent, compact conformation. This binding mode is similar to those found in its complexes with some low-affinity kinases and a quinone reductase, being strikingly different from the extended conformation of IMT in its high-affinity kinase targets.",
keywords = "α -Acid glycoprotein, Fluorescence quenching, Genetic variants, Imatinib, Induced circular dichroism, Protein binding",
author = "I. Fitos and A. Simon and F. Zsila and G. M{\'a}dy and A. Bencsura and Z. Varga and L. Őrfi and G. K{\'e}ri and J. Visy",
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T1 - Characterization of binding mode of imatinib to human α 1-acid glycoprotein

AU - Fitos, I.

AU - Simon, A.

AU - Zsila, F.

AU - Mády, G.

AU - Bencsura, A.

AU - Varga, Z.

AU - Őrfi, L.

AU - Kéri, G.

AU - Visy, J.

PY - 2012/4/1

Y1 - 2012/4/1

N2 - Imatinib (IMT) is a selective tyrosine kinase inhibitor, used in the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Its strong plasma protein binding was found to belong to the F1*S genetic variant of α 1-acid glycoprotein (AGP). In this work, comparative AGP binding studies were performed with IMT fragment molecules to reveal which parts of the molecule are important in the high-affinity interaction provoking specific spectral changes. Molecular modeling calculations indicated that IMT docked into the X-ray structure of AGP/F1 adopts a bent, compact conformation. This binding mode is similar to those found in its complexes with some low-affinity kinases and a quinone reductase, being strikingly different from the extended conformation of IMT in its high-affinity kinase targets.

AB - Imatinib (IMT) is a selective tyrosine kinase inhibitor, used in the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Its strong plasma protein binding was found to belong to the F1*S genetic variant of α 1-acid glycoprotein (AGP). In this work, comparative AGP binding studies were performed with IMT fragment molecules to reveal which parts of the molecule are important in the high-affinity interaction provoking specific spectral changes. Molecular modeling calculations indicated that IMT docked into the X-ray structure of AGP/F1 adopts a bent, compact conformation. This binding mode is similar to those found in its complexes with some low-affinity kinases and a quinone reductase, being strikingly different from the extended conformation of IMT in its high-affinity kinase targets.

KW - α -Acid glycoprotein

KW - Fluorescence quenching

KW - Genetic variants

KW - Imatinib

KW - Induced circular dichroism

KW - Protein binding

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