Summary
Researchers at the Paul Scherrer Institute PSI and the University of Zurich have deciphered a previously unknown protein structure of the cancer-relevant B-Raf protein. The study, published in Molecular Cell, demonstrates how B-Raf mutations – which cause approximately 50% of all melanomas and 7% of other cancer types – uncontrollably activate cell division through asymmetric dimer formation. The high-resolution visualization of the B-Raf-MEK1 complex opens new avenues for targeted cancer medications.
People
- Dr. Yasushi Kondo (First author, PSI Center for Life Sciences)
- Prof. Dr. Jörg Standfuss (PSI Center for Life Sciences)
Topics
- Cancer research / Molecular biology
- B-Raf protein and signal transduction
- Drug development
- Melanoma and cancer resistance
Clarus Lead
B-Raf mutations are among the most common genetic drivers of aggressive cancer types, yet available therapies quickly lose their effectiveness. The new structural elucidation directly addresses this treatment gap: With the first successful atomic resolution of the active B-Raf-MEK1 complex, pharmaceutical researchers can now design more precise active compounds that target alternative binding sites and overcome resistance development. This could substantially expand the therapeutic spectrum for millions of patients with B-Raf-positive tumors.
Detailed Summary
B-Raf is a central regulatory protein in human signal cascades that controls cell growth and cell division. Mutated B-Raf variants remain permanently switched to "green" – independent of biological control signals – thus driving uncontrolled tumor growth. Particularly insidious: Cancer cells typically develop resistance to available B-Raf inhibitors within a few months.
The research group led by Kondo investigated the molecular structure of B-Raf dimers using synchrotron crystallography at the Swiss Light Source SLS and at Diamond Light Source in England, supplemented by cell biology experiments. They identified an asymmetric dimer form in which the so-called NtA sequence motif of one B-Raf protein extends like a connecting bridge to its partner. Crucially: This structure binds directly to the downstream protein MEK1, which triggers the next signal transmission. The high-resolution visualization of this ternary B-Raf-MEK1 complex was previously not possible.
This structural insight enables rational drug design: Precise inhibitors can specifically target the newly characterized binding surfaces and thus interrupt signals without activating existing resistance mechanisms. The PSI team is already searching for molecules that block the B-Raf-MEK1 complex – an approach that could diversify the available therapeutic arsenal.
Key Statements
- B-Raf mutations drive approximately 50% of all melanomas and 7% of other cancer types; current therapies quickly lose their effectiveness.
- First atomic resolution of the active B-Raf-MEK1 signaling complex opens new design principles for inhibitors.
- Structural insights into NtA-mediated asymmetric dimers could overcome resistance development and multiply treatment options.
Critical Questions
Evidence & Validation: The structure was confirmed at synchrotron facilities and in cell culture – how robust are these data for extrapolation to tumors in vivo, where more complex cellular contexts are at play?
Translation Gap: How long does the typical path from structural elucidation to clinically tested active compounds typically take? What obstacles might arise in the development of new B-Raf-MEK1 inhibitors?
Resistance Mechanisms: The study addresses resistance to existing B-Raf inhibitors – but do escape mutations also develop against new compounds targeting the B-Raf-MEK1 complex, and how could this be prevented?
Selectivity & Side Effects: B-Raf and MEK1 are active in all human cells – how can selectivity for tumor cells be ensured to minimize toxicity in healthy tissue?
Commercialization & Access: Who bears the costs for further developing these findings? How is it ensured that resulting therapies are available and affordable worldwide?
References
Primary Source: Mechanism of MEK1 phosphorylation by the N-terminal acidic motif-mediated asymmetric BRAF dimer – Y. Kondo et al., Molecular Cell, 21.07.2026
Press Release: Fighting Cancer Growth – Paul Scherrer Institute PSI, 21.07.2026
Verification status: ✓ 21.07.2026
This text was created with the support of an AI model.
Editorial responsibility: clarus.news | Fact-checking: 21.07.2026