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Asp746 to glycine change may have a greater influence than Cys751 to serine change in accounting for ligand

Shantaram A Kamath1, John K Buolamwini

  • 1Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 847 Monroe Ave, Suite 327, Memphis, TN 38163, USA.

Journal of Computer-Aided Molecular Design
|September 27, 2005
PubMed
Summary
This summary is machine-generated.

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Molecular dynamics simulations reveal distinct ATP-binding channel dynamics in EGFR and HER-2. Differences in key residue interactions, particularly involving Asp746 in EGFR, influence channel opening and may explain inhibitor selectivity between these receptor tyrosine kinases.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Computational Chemistry

Background:

  • Epidermal growth factor receptor (EGFR) and Human Epidermal growth factor Receptor 2 (HER-2) are key targets in cancer therapy.
  • Understanding the structural basis of their ATP-binding sites is crucial for developing selective inhibitors.

Purpose of the Study:

  • To investigate the molecular dynamics of ATP-bound EGFR and HER-2 kinase domains.
  • To explore how amino acid residue variations near the ATP site affect kinase selectivity for inhibitors.

Main Methods:

  • Performed up to 8.0 ns molecular dynamics simulations.
  • Analyzed ATP-bound complexes of EGFR and a homology model of HER-2.
  • Focused on amino acid residue changes in or near the ATP binding site.

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Main Results:

  • Simulations showed a channel forming under Thr766 in EGFR due to Gln767 side chain movement.
  • In HER-2, Gln799 moved similarly, but Arg784 moved towards the hinge, closing the channel.
  • The absence of EGFR's Asp746 (replaced by Gly778 in HER-2) affects Arg784 positioning and channel accessibility.

Conclusions:

  • The interaction between Asp746 and Arg784 in EGFR helps maintain an open ATP-binding channel.
  • HER-2's channel tends to close due to Arg784 movement, influenced by the Gly778 substitution.
  • These structural differences, rather than the Cys751 to Ser751 change, likely contribute significantly to ligand selectivity between EGFR and HER-2.