The paper describes the consequences on the activity and structure of oncogenic mutants of a protein kinase. The structure of B-RAF is in complex with an inhibitor, providing insights into mechanisms of B-Raf inhibition. The paper provides a rational explanation of how mutations that occur in human cancer activate B-RAF. The paper defines a new paradigm of oncogene activation whereby the mutant protein is able to transactivate a family member (C-Raf) which is not mutated.

Yes, several labs have tried for over 10 years to crystallize Raf kinase.

Marais's lab has been working on Raf biology for several years. Barford's lab has been involved in structural aspects of signaling for many years. The collaboration with the human Cancer Genome Project led to a focused effort on B-RAF.

B-Raf is mutated in 70% of malignant melanoma and a number of other cancers. Most of these mutations activate B-Raf in vivo, and drive the growth of human tumors. This work provides insights into the biology of how mutant B-Rafs work in cancer. The structure provides a view of the three-dimensional shape of the protein, which will be quite valuable in drug discovery programs that aim to develop anti-B-Raf drugs for the treatment of cancer.