Newly Discovered BRAF Protein Conformation Offers Fresh Target for Cancer Drug Development
核心洞察
Researchers at the Paul Scherrer Institute (搜索) have resolved a previously unknown asymmetric BRAF (搜索) dimer conformation that forms during cell signaling, published in Molecular Cell.
The study provides the first high-resolution visualization of the active BRAF (搜索)-MEK1 (搜索) complex, revealing how the NtA sequence motif bridges two BRAF proteins of different shapes.
BRAF (搜索) mutations drive roughly half of all melanomas and about seven percent of other cancers, with existing targeted therapies frequently losing effectiveness due to drug resistance.
A team of researchers at the Paul Scherrer Institute (搜索) (PSI) and the University of Zurich has resolved a previously unknown conformation of the BRAF (搜索) protein, a key driver in multiple aggressive cancers, offering a new structural blueprint for drug development. The findings, published in the journal Molecular Cell, represent the first high-resolution visualization of the active BRAF-MEK1 (搜索) complex in its working form.
Around half of all malignant melanomas and approximately seven percent of all other cancers carry mutations in BRAF (搜索), a protein that functions as a critical switch in the signaling pathway regulating cell growth and division. When mutated, BRAF behaves like "a traffic light that's always green," sending constant proliferative signals that drive uncontrolled tumor growth regardless of upstream regulatory cues.
"Cancerous tumours affected by BRAF (搜索) mutations are considered particularly aggressive and difficult to treat," said Yasushi Kondo, a researcher at the PSI Center for Life Sciences and lead author of the study. Currently, very few active substances are available for targeted treatment of these tumors, and cells typically develop resistance to these drugs after only a few months.
Uncovering an Asymmetric Dimer
Using the Swiss Light Source SLS at PSI and the Diamond Light Source in Didcot, England, alongside cell-based experiments at the University of Zurich, the researchers investigated the molecular structure of BRAF (搜索) dimers in unprecedented detail. They discovered a previously unknown form of BRAF dimer that forms during the signaling cascade, consisting of two BRAF proteins of different shapes. In this asymmetric arrangement, the NtA sequence motif of one BRAF protein extends toward its partner, forming a bridge that connects the two.
Crucially, the team did not examine this asymmetric dimer in isolation. They captured it in complex with MEK1 (搜索), the next protein in the signaling chain. "This interaction with MEK1 is a crucial step in the signaling cascade leading to cell division," Kondo explained. Once activated, MEK1 moves on to relay the proliferative signal downstream.
"In this study, we succeeded for the first time in producing a high-resolution visualisation of the exact structure of this complex in its active, working form, which consists of the two BRAF (搜索) proteins linked asymmetrically via NtA and the MEK1 (搜索) protein," said Kondo.
Implications for Drug Design
The structural insights carry direct implications for therapeutic development. Targeted agents work by binding to active components of a signaling pathway, interrupting signal transmission and effectively setting one of the traffic lights to red. "The more precisely we know the structure of these components, the more precisely we can design drugs that fit perfectly," Kondo noted.
The researchers at the PSI Center for Life Sciences are already searching for molecules that bind to the newly characterized BRAF (搜索)-MEK1 (搜索) complex and could interrupt the unwanted signaling that drives tumor proliferation. "Our findings open up new possibilities for developing drugs that target BRAF in new, different ways," Kondo said. "Having a broader range of compounds could provide more options for treatment and help address the diverse ways in which cancers evade existing therapies."
The study was supported by the Swiss Cancer Research Foundation. The hope is that a wider range of more effective therapeutic agents targeting BRAF (搜索) will become available, providing clinicians with additional options when resistance to current therapies inevitably develops.