Till startsida
Sitemap
To content Read more about how we use cookies on gu.se

Defects in the calcium-binding region drastically affect the cadherin-like domains of RET tyrosine kinase

Journal article
Authors Chunxia Gao
Morten Grøtli
Leif A Eriksson
Published in Physical Chemistry Chemical Physics
Volume 18
Issue 12
Pages 8673-8681
ISSN 1463-9076
Publication year 2016
Published at Department of Chemistry and Molecular Biology
Pages 8673-8681
Language en
Links dx.doi.org/10.1039/c6cp00042h
Keywords PARTICLE MESH EWALD, HIRSCHSPRUNG-DISEASE, EXTRACELLULAR DOMAIN, MOLECULAR-DYNAMICS, RECEPTOR, CANCER, MUTATIONS, MODEL, SIMULATIONS, ACTIVATION
Subject categories Biochemistry and Molecular Biology

Abstract

Mutations in the rearranged during transfection (RET) tyrosine kinase gene leading to gain or loss of function have been associated with the development of several human cancers and Hirschsprung's disease (HSCR). However, to what extent these mutations affect individual bio-molecular functions remains unclear. In this article, the functionally significant mutations in the RET CLD1-4 calcium-binding site which lead to HSCR, and depletion of calcium ions in the RET CLD1-4 calcium binding site, were investigated by molecular dynamics simulations - to understand the mechanistic action of the mutations or loss of calcium ions in altering the protein kinase structure, dynamics, and stability. The mutations or loss of calcium ions change the local conformation and change the free energy landscape. Specifically, the mutations and loss of calcium ions decrease the radius of gyration of the whole structure, leading to improper protein folding and GFL-GFR alpha contact site reduction. Furthermore, based on the most populated conformation in the wildtype MD simulations, a pharmacophore was generated by fragment docking to identify key features of the possible inhibitors targeting the calcium binding site. Overall, the findings may provide useful structural insights into the molecular mechanism underlying RET calcium-binding site mutations and assist in development of novel drugs targeting the extracellular ligand contact site of wildtype RET.

Page Manager: Webmaster|Last update: 9/11/2012
Share:

The University of Gothenburg uses cookies to provide you with the best possible user experience. By continuing on this website, you approve of our use of cookies.  What are cookies?