How changes to proteins can alter drug interactions for new precision therapies Scripps Research team maps how chemical modifications to proteins affect drug binding across the human proteome.
May 05, 2026
LA JOLLA, CA Inside every human cell, proteins are constantly being tagged with small chemical modifications after they're produced. Known as post-translational modifications, or PTMs, these can change how a protein folds, where it travels and how it behaves. Now, scientists at Scripps Research have shown that PTMs also play a major role in determining whether proteins can bind to drug-like molecules.
The study, published in Nature Chemical Biology on May 5, 2026, identified more than 400 proteins whose ability to engage drug-like molecules is dictated by their modification state. The findings suggest that the same protein can be more or less druggable depending on which PTMs it carries an insight that could reshape how new therapies are developed.
We already know PTMs affect protein structure and function, says senior author Christopher Parker, a professor and The Abide-Vividion Chair in Chemistry and Chemical Biology at Scripps Research. We asked: if we perturb a class of PTMs, what's the broad impact on proteome-wide druggability?
The team used specially designed chemical probes: small, drug-like molecules that can be locked onto the proteins they bind. By applying these probes in living cells under conditions that altered two of the most common PTMs phosphorylation and N-linked glycosylation the researchers could map which proteins became easier or harder for small molecules to access depending on their modification state.
Of more than 5,000 proteins screened, the affected targets spanned enzymes, ion channels, transcription factors and epigenetic regulators, including many that have historically resisted drugs. In many cases, the PTMs were physically located near the binding sites they affected, directly reshaping pockets that drug-like molecules could occupy. In other cases, PTMs altered how proteins interact with each other, revealing new binding sites in the process.
Among the most consequential findings involved KRAS, one of the most frequently mutated proteins in human cancer and the target of several recently approved drugs, including sotorasib and adagrasib for KRAS G12C-mutant non-small cell lung cancer (NSCLC). The researchers found that phosphorylation at specific sites on KRAS significantly affected how well clinical inhibitors bound and inhibited the protein. This could help explain why KRAS inhibitors don't work equally well across all patients, and suggests a tumor's PTM status could factor into how these therapies are selected or combined.
Even with a small searchlight, we found that one small PTM on one site dramatically affects the activity of known inhibitors for one of the most sought-after drug targets in cancer, says Parker. Those inhibitors work well in patients, but maybe they could work better.
The findings also pointed beyond cancer. Among the targets identified was NPC2, a protein whose malfunction causes Niemann-Pick disease, a rare and fatal condition. In that case, a single sugar-based PTM turned out to determine whether drug-like molecules could bind.
PTMs are another layer of variables that we should be considering more in drug discovery, says Parker.
By identifying which PTM states of a protein are most druggable, researchers may be able to design more selective treatments with fewer off-target effects. Many of the proteins identified in the study lack known drug candidates, which could point to untapped opportunities.
The researchers plan to extend their method to other types of PTMs and to more disease-relevant systems, using larger and more chemically diverse probe libraries to improve coverage of the proteome.
Our vision would be to broadly achieve disease-state-specific pharmacology, says Parker. PTM status could be a way to selectively target a protein in a disease cell, finding vulnerabilities like unique chinks in the armor of a disease.
This study was co-led by staff scientist Weichao Li and graduate student Qijia Wei. In addition to Parker, Li and Wei, authors of Posttranslational modifications remodel proteome-wide ligandability, include Manuel Llanos, Clara Gathmann, Paolo Governa, Tzu-Yuan Chiu, Jacob M. Wozniak, Appaso M. Jadhav, Matthew Holcomb, Jacob Cravatt, Mia L. Huang and Stefano Forli of Scripps Research; and Ashok Dongre of Bristol Myers Squibb.
Support for this study was provided by the National Institute of Allergy and Infectious Diseases (grants R01AI156268 and R01AI182439); the National Institute of General Medical Sciences (grant R35GM142462); and the Chan Zuckerberg Initiative (grant 2023-332369).
Chemistry Parker, Christopher
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How changes to proteins can alter drug interactions for new precision therapies Scripps Research team maps how chemical modifications to proteins affect drug binding across the human proteome.
