Email updates

Keep up to date with the latest news and content from BMC Structural Biology and BioMed Central.

Open Access Highly Accessed Research article

An in silico study of the molecular basis of B-RAF activation and conformational stability

Filip F Fratev* and Svava Ósk Jónsdóttir

Author affiliations

Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet, Building 208, DK-2800 Kongens Lyngby, Denmark

For all author emails, please log on.

Citation and License

BMC Structural Biology 2009, 9:47  doi:10.1186/1472-6807-9-47

Published: 22 July 2009

Abstract

Background

B-RAF kinase plays an important role both in tumour induction and maintenance in several cancers and it is an attractive new drug target. However, the structural basis of the B-RAF activation is still not well understood.

Results

In this study we suggest a novel molecular basis of B-RAF activation based on molecular dynamics (MD) simulations of B-RAFWT and the B-RAFV600E, B-RAFK601E and B-RAFD594V mutants. A strong hydrogen bond network was identified in B-RAFWT in which the interactions between Lys601 and the well known catalytic residues Lys483, Glu501 and Asp594 play an important role. It was found that several mutations, which directly or indirectly destabilized the interactions between these residues within this network, contributed to the changes in B-RAF activity.

Conclusion

Our results showed that the above mechanisms lead to the disruption of the electrostatic interactions between the A-loop and the αC-helix in the activating mutants, which presumably contribute to the flipping of the activation segment to an active form. Conversely, in the B-RAFD594V mutant that has impaired kinase activity, and in B-RAFWT these interactions were strong and stabilized the kinase inactive form.