The hidden form was always there. Now it can be seen.
For decades, scientists pursued the p38a protein as a key to treating cancer, inflammation, and neurodegeneration — yet every promising drug fell short. A team at IRB Barcelona has now revealed why: the protein quietly inhabits a second, oxidized form, sealed shut by a disulfide bridge, that no existing database had ever recorded. Because researchers were always studying p38a under conditions that erased this hidden state, they were designing drugs against a target that, in living cells, sometimes does not exist as they imagined it. The incomplete map, not the destination, was the problem all along.
- Decades of drug development targeting p38a have failed to produce effective treatments for cancer, inflammation, and neurodegeneration — a costly and persistent mystery now demanding explanation.
- IRB Barcelona researchers discovered that p38a can fold into a dormant, oxidized form sealed by a disulfide bridge, rendering it functionally inert — a state entirely absent from all 357 structures in the global Protein Data Bank.
- The blind spot was structural: standard laboratory techniques use reducing agents that chemically erase the oxidized form before it can be observed, meaning drug designers were unknowingly working from an incomplete portrait of their target.
- The oxidized form is transient and difficult to capture, but its very instability is now a scientific opportunity — it exposes new molecular cavities that could serve as precise drug-binding sites.
- Researchers are now mapping these newly revealed pockets, with the potential to design inhibitors that avoid the protein's catalytic core, reducing side effects and reshaping how an entire family of cellular enzymes is approached therapeutically.
For decades, pharmaceutical researchers targeted the p38a protein as a promising intervention point for cancer, chronic inflammation, and neurodegeneration. The enzyme sits at the center of cellular self-regulation, making it an obvious candidate. Yet inhibitors kept failing to deliver, and no one could fully explain why.
A team led by Dr. Maria Macias and Dr. Angel R. Nebreda at IRB Barcelona has now uncovered the reason. They discovered that p38a exists in a previously undescribed dormant state, produced when the protein undergoes oxidation. In this form, a disulfide bridge forces the protein to fold in a way that seals its active binding sites shut, rendering it inert — until reducing cellular conditions reverse the transformation and restore its function.
The finding, published in Nature Communications, exposes a fundamental gap in the field's foundation. All 357 p38a structures in the Protein Data Bank represent only the reduced, active form — not because the oxidized form is rare, but because standard structural techniques rely on reducing agents that chemically prevent oxidation from occurring. Researchers were studying a protein locked into one state, then designing drugs to attack a form that living cells do not always present.
Lead authors Dr. Joan Pous, Dr. Pau Martin Malpartida, and doctoral student Blazej Baginski note that oxidized protein forms are inherently difficult to study, appearing and vanishing with shifts in the cell's redox environment. Yet this elusiveness carries a therapeutic promise: the oxidized form reveals new molecular cavities — surfaces that do not exist in the reduced state — which could serve as precise drug targets, avoiding the protein's catalytic core and reducing unwanted side effects.
The research, conducted in collaboration with Dr. Modesto Orozco's structural biology group and the biotech firm Nostrum Biodiscovery, will now focus on mapping and pharmacologically testing these newly visible pockets. If successful, the implications extend beyond p38a to the broader kinase family — the enzymes that govern cellular signaling. The hidden form was always present. Now that it has been seen, the search for better drugs can begin from a truer picture.
For decades, pharmaceutical researchers have chased p38a protein as a target for treating cancer, chronic inflammation, and neurodegenerative disease. The enzyme sits at the center of how cells regulate themselves, making it an obvious candidate for intervention. Yet despite sustained effort from major drug companies and academic labs worldwide, the inhibitors they developed kept failing to deliver the promised results. The problem, it turns out, was not the researchers' ambition or skill. They were simply looking at an incomplete picture.
A team led by Dr. Maria Macias and Dr. Angel R. Nebreda at IRB Barcelona has now identified why. The two ICREA researchers discovered that p38a exists in a form no one had formally described before—a dormant state that emerges when the protein undergoes a chemical transformation called oxidation. In this configuration, a disulfide bridge forms within the protein's structure, forcing it to fold in a way that seals shut the binding sites where activators and substrates normally attach. The protein becomes inert. It cannot do its job. And the change is reversible: when cellular conditions shift back toward a reducing state, the protein unfolds and regains its function.
The finding, published in Nature Communications, reframes a fundamental problem in drug design. The Protein Data Bank—the global repository of protein structures—holds 357 documented structures of p38a. Every single one represents the protein in its reduced, active form. This uniformity was not accidental. Most structural studies of proteins rely on experimental techniques that include reducing agents, chemical compounds that prevent oxidation. Researchers were essentially studying p38a under conditions that locked it into one state, never seeing the other. When drug developers then built inhibitors based on these structures, they were designing molecules to target a protein that, in living cells, sometimes simply does not exist in the form they were attacking.
Drs. Joan Pous, Pau Martin Malpartida, and doctoral student Blazej Baginski, the study's lead authors, acknowledge the complexity of this discovery. Oxidized forms of proteins are notoriously difficult to study because they are transient—they appear and disappear depending on the cell's redox environment, the balance between oxidative stress and reducing conditions. Yet this very elusiveness may hold the key to better drugs. The oxidized form of p38a presents new interaction cavities, pockets and surfaces that do not exist in the reduced state. These could become targets for inhibitors that disable the protein without touching its catalytic center, the core machinery that drives its function. Such precision would mean fewer off-target effects, fewer side effects, and potentially more effective treatments.
The work emerged from collaboration between Macias and Nebreda's lab, the structural biology group of Dr. Modesto Orozco at IRB Barcelona and the University of Barcelona, and the biotech firm Nostrum Biodiscovery, with funding from Spanish and European research agencies and the BBVA Foundation. The researchers' next phase will focus on mapping those new cavities in the oxidized form and testing whether they can be exploited pharmacologically. If successful, the discovery could reshape how scientists approach not just p38a but other kinases—the large family of enzymes that regulate cellular signaling. The hidden form was always there. Now that it has been seen, the hunt for better drugs can begin in earnest.
Notable Quotes
The study of kinases in their oxidised forms is complex, but the key to addressing them effectively from a pharmacological perspective may lie in these forms.— Drs. Joan Pous, Pau Martin Malpartida, and Blazej Baginski, lead authors
This new form illustrates a mechanism of action of p38a regulated by the cellular redox state, thereby explaining biochemical observations described to date but with no structural molecular basis.— Research team findings
The Hearth Conversation Another angle on the story
So researchers have been trying to inhibit p38a for years without success. What was actually going wrong?
They were designing drugs against a protein that only exists in one form—the active, reduced state. But p38a also adopts an inactive, oxidized form that they'd never formally characterized. Every structure in the database showed only the active version.
Why didn't anyone see this oxidized form before?
The experimental techniques used to study protein structures rely on reducing agents—chemicals that prevent oxidation. So researchers were inadvertently locking the protein into its active state before they even looked at it. They never had the chance to see the other form.
And this oxidized form is actually inactive?
Completely. A disulfide bridge forms, the protein folds differently, and the binding sites seal shut. The protein can't interact with the molecules that normally activate it. It's a natural off switch.
Is it permanent?
No, that's the elegant part. It's reversible. When the cell's redox conditions change—when reducing conditions return—the protein unfolds and becomes active again. It's a temporary state, but it's real and it matters.
So what does this mean for drug design going forward?
The oxidized form has new cavities and surfaces that don't exist in the active form. Those could become targets for more specific inhibitors—drugs that disable the protein without disrupting its core catalytic machinery. That means potentially fewer side effects and better therapeutic outcomes.