Targeted protein degradation (TPD) represents an emerging class of therapeutics that selectively degrades disease-relevant proteins.

For example, targeted degradation of oncoproteins in a tumor can inhibit tumor growth while minimizing the toxic side effects of traditional chemotherapy. The degradation relies on the endogenous mammalian ubiquitin ligase pathway, specifically through the use of proteolysis targeting chimera (PROTAC) molecules which recruit E3 ligases to target proteins for ubiquitination. However, TPD strategies are hindered by the limited number of E3 ligases with useful targets.

In a recent study from the , the authors leverage an NMR-based fragment screening protocol to identify new targets for E3 ligases. The work focused specifically on the E3 ligase Kelch-like protein 12 (KLHL12), which is overexpressed in cancer cell lines as compared to healthy tissue.

In summary, 13,824 fragments were screened for binding to KLHL12, 35 compounds showed significant shifts in the NMR spectra, and 15 of those had shifts corresponding to the KLHL12 binding pocket. Of these 15, Benzimidazole 1 was identified as the compound with the strongest binding affinity (150 µM). To increase the binding affinity even further, a collection of close structural analogs to benzimidazole 1 were synthesized, characterized, and modified.

Eventually, the researchers created benzimidazole 7k, which was shown by X-ray crystallography to bind KLHL12 in a similar pose to known ligands. Furthermore, benzimidazole 7k bound KLHL12 with submicromolar affinity (0.33 µM) as determined by surface plasmon resonance. Additional structural modifications were made in an effort to further increase binding affinity, namely by occupying more of the binding cleft, but few compounds matched the binding strength of benzimidazole 7k.

To determine the feasibility of benzimidazole derived compounds as PROTACS, the specificity of benzimidazole derivatives for KLHL12 was then assessed. Overlay of benzimidazole 7k-bound KLHL12 crystal structures with other KLHL family members indicated that poor binding pocket sequence homology and steric hinderance would likely prevent benzimidazole 7k from binding most other KLHL proteins. KLHL8, KLHL18, and KLHL19 had high degrees of sequence similarity, but fluorescence polarization anisotropy of benzimidazole 11a and KLHL19 indicated very weak binding.

Therefore, benzimidazole derived compounds likely have a high degree of specificity for KLHL12 within the KLHL family. Additionally, when tested against endogenous KLHL12 in HEK293 cells, benzimidazole derivatives were found to bind KLHL12 in both permeabilized and live cells with submicromolar affinities.

While the identification of tight-binding targets for the E3 ligase KLHL12 is only the first step towards a new TPD therapy, this study provides key methodological and structural insights into the development of PROTAC molecules and paves the way for future KLHL12-targeting drug design.

Make sure to check out the full story in the !

Martin Egli, the Richard N. Armstrong, Ph.D. Professor of Innovation in Biochemistry and a professor of biochemistry, delivered the Kairos Lecture on May 28.

His scientific accomplishments have resulted in over 300 publications and two influential nucleic acid textbooks, and he has received major honors and extensively served his department and the university.

His Kairos lecture, RNA Structure, Etiology and Re-Engineering Into siRNA Therapeutics, highlighted how the 2’-hydroxyl group on RNA sugar (ribose) increases chemical and conformational diversity, affecting stability, function, and enabling more varied base pairing than DNA. He explained that, as RNA has a vast folding landscape and limited 3D structural and sequence data, structure  prediction hasn’t reached a transformative “RNA AlphaFold” stage, an observation made in reference to AlphaFold role in revolutionizing protein structure prediction.

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�Ӱ�ԭ�� the Kairos Lecture Series

The School of Medicine Basic Sciences host the Kairos Lectures to expose �Ӱ�ԭ�� basic and biomedical research community to the exciting research our colleagues are doing. The Greek term kairos refers to the opportune, critical, or right moment for action. Kairos Lectures are an invitation for our community to recognize the moments that matter: the right time to learn something new, connect across expertise, and move science forward together.

Congratulations to William R. Kenan, Jr. Chair, Professor of Biological Sciences and CSB researcher Brandt Eichman on being the first �Ӱ�ԭ�� faculty member to be awarded the prestigious .

The fellowship, jointly funded by the the Royal Society and the Wolfson Foundation, invites outstanding international researchers to a UK university or research institution to foster collaborative connections and enrich global scientific research.

Eichman fellowship officially began March 15, 2026, and will run until December 15, 2027. He is a visiting fellow at Clare Hall College at the University of Cambridge, and his research aims to understand how cells repair and tolerate chemically modified, or “damaged,” DNA during replication.

Read more about this .

A new study from the reveals that even the ribosome, one of the most intensively studied molecular machines in biology, still holds hidden surprises. They have uncovered a previously undetected chemical modification in a key ribosomal protein, uL16, in which a single oxygen atom in the protein backbone is replaced by sulfur, a rare change known as thioamidation. This modification sits near the ribosome catalytic core, where proteins are assembled, placing it in a position that could subtly influence how genetic information is translated into functional molecules.

The discovery emerged from a combination of cutting-edge computational and experimental approaches. Using AlphaFold3, the team screened thousands of proteins in Escherichia coli to identify potential interaction partners for an enigmatic enzyme called YcaO. The analysis pointed to uL16 as a likely target, a prediction that was confirmed through genetic knockouts and biochemical experiments. When the gene encoding YcaO was removed, the sulfur modification disappeared. Reintroducing the enzyme restored it. Further experiments showed that YcaO can directly install the modification, but only when uL16 is in its fully folded form, indicating that the enzyme recognizes the overall shape of the protein rather than a short sequence of amino acids.

This finding challenges the prevailing view of YcaO enzymes, which were thought to act mainly on small, flexible peptides involved in natural product biosynthesis. Instead, this work shows that YcaO can modify large, structured proteins, suggesting a broader role for this enzyme family in cell biology. The modification also appears to work in concert with a neighboring chemical change on uL16, hinting at a coordinated system for fine-tuning ribosome function. Although cells lacking the modification grow normally under standard conditions, subtle effects emerge under nutrient limitation, pointing to a role in adapting protein synthesis to environmental stress.

The implications extend far beyond a single bacterium. By analyzing related enzymes across genomes, the researchers predict that this sulfur-based modification is widespread among bacteria, including important human pathogens such as Klebsiella pneumoniae and Pseudomonas aeruginosa, a finding they confirmed experimentally. This suggests that thioamidation is not an oddity but a conserved feature of bacterial ribosomes that has gone unnoticed until now.

More broadly, the study highlights how much remain to be discovered, even in systems long considered well understood. A tiny chemical swap, invisible to standard detection methods, turns out to be both common and potentially significant. The work also showcases the growing power of artificial intelligence in biology, with structural prediction tools guiding researchers toward new biochemical insights. As similar approaches are applied more widely, many more hidden modifications may come to light, reshaping our understanding of the molecular machinery of life and opening new possibilities for targeting it in medicine.

Read the full story at !

Pre-clinical studies have shown that PROTACs can develop resistance when mutations occur in the E3 ligase being used, only to be rescued when a different E3 ligase-based PROTACs is used. The resistance compounds with the fact that the commonly used E3 ligases, cereblon (CRBN) and von Hippel Lindau (VHL) can have increased off-target effects and restricted chemical design, respectively. Therefore, expanding the availability of E3 ligases for PROTAC therapy is necessary for the development of future PROTACs not only to increase diversity of the therapy but also minimize off-target effect and allow for more flexibility in the design.

This led �Ӱ�ԭ�� postdoc Dr. Jade Katinas, of the , and colleagues to the protein fem-1 homolog B (FEM1B). FEM1B recognizes substrate in the Cullin-RING E3 ligase, which is found in most cells and is crucial in maintaining the balance of proteins with roles in redox sensing and management. To achieve this, it is thought that FEM1B has multiple recognition sites for binding to substrates with interesting structural aspects in the binding pocket that induces strong interactions.

Previous library screening with FEM1B had shown that it has good potential as a degrader, thus the researchers aimed to run an NMR-based fragment screen to try and identify small molecules that bind to FEM1B. Due to protein instability the team had to develop multiple mutants of the protein, however, once they overcame this, 1H‐13C HMQC spectra using selective 13C‐methyl labeling of Leu, Ile, Val, and Met sites of FEM1B was performed and several hits were identified.

These hits were then characterized by X-ray co-crystal structures. These FEM1B co-crystals structures gave valuable insight into the binding potential of these fragments. One molecule (VU0416476) was found to mimic previously known ligands by binding covalently to a cysteine residue, while the other identified hits bound non-covalently, the first reported of its kind.

This research is exciting, as it offers a starting template for discovering new forms of PROTACs, especially for proteins such as FEM1B.

You can learn more about this work in .

A group of �Ӱ�ԭ�� researchers, led by the Lacy lab, developed a novel vaccination approach that cleared the harmful gut bacterium C. diff in an animal model of infection.

about this major step forward for C. diff vaccine development at �Ӱ�ԭ�� Health News.

LQTS is a fatal disorder linked to syncope, arrhythmia, and cardiac arrest. Type 1 Long QT syndrome (LQT1) accounts for close to half of congenital LQTS and is caused by loss-of-function mutations in the voltage-gated potassium channel KCNQ1.

The Sanders lab recently investigated whether a small molecule could help these channel proteins work better, with a goal that one day it might help treat long QT syndrome.

Read more about this study on the .

Dr. Iva Chitrakar, a postdoc in the lab of Dr. Breann Brown, states that this underscores the critical need to understand ALAS2 regulation. Little is known about ALAS within the mitochondrial matrix, where heme biosynthesis occurs. Dr. Chitrakar identified a reversible mechanism by which heme inhibits its own synthesis by affecting mature mitochondrial ALAS2 activity. Inactivating ALAS2 is inactivated in the presence of heme stress in order to reduce heme synthesis, a new form of negative feedback in heme biosynthesis.

The regulation of ALAS2 is an intricate, multifaceted process where heme acts as an allosteric effector to maintain cellular homeostasis. These findings support a model where the presence of multiple heme-binding sites within the enzyme likely serves as a fail-safe mechanism so that ALAS2 can still interact with heme even if one site fails. Since the ALAS2 homodimer contains multiple nonequivalent heme-binding sites, the enzyme can redundantly tune its activity, likely by inducing conformational changes that block substrate binding or by recruiting the CLPXP protease for targeted degradation. This inhibitory mechanism may also extend to the “heme synthesis metabolon,” a complex of mitochondrial proteins that optimizes metabolic flux. By combining this rapid allosteric inhibition with slower, irreversible degradation, the cell can precisely calibrate heme production to support its vital biological functions.

You can find more about this study in the !

The study showed that a protein language model could design functional human antibodies that recognized the unique antigen sequencies (surface proteins) of

specific viruses, without requiring part of the antibody sequence as a starting template.

Read more about to thwart novel viruses.

Martin Egli, professor of biochemistry, has been awarded the Richard Armstrong Professorship of Innovation in Biochemistry. “Martin is an internationally recognized scholar and highly deserving of this honor,” said Biochemistry Department Chair David Cortez.

Dr. Egli earned his undergraduate and doctoral degrees in Chemistry from ETH Zurich and completed postdoctoral training at MIT in the Alexander Rich lab, becoming a world expert in x‑ray crystallography of nucleic acids and protein–nucleic acid complexes. He joined �Ӱ�ԭ�� as an assistant professor in 1995 and became professor of biochemistry in 2005.

Dr. Egli research spans the structures and functions of nucleic acids and their therapeutic applications, with over 300 publications that have garnered more than 13,000 citations. His landmark contributions include stabilizing RNAs for therapeutic delivery, elucidating how DNA polymerases process damaged DNA, and defining mechanisms of RNA‑modifying enzymes; he ranks in the top 0.05% of scholars worldwide per 2024 ScholarGPS.

In addition to his research, he co–edited the definitive 2022 volume Nucleic Acids in Chemistry and Biology and authored a 2012 book on artificial nucleic acids—works that underpin advances such as mRNA vaccines and siRNA therapeutics. His honors include election as an AAAS Fellow (2006), the Alexander Rich Award Lecture (2013), and election to the European Academy of Sciences and Arts (2023). He has served the Biochemistry department and university through faculty searches, mentoring and awards committees, the School of Medicine FAPC, and as Scientific Director of the CSB X‑ray crystallography facility. A dedicated educator, he co-leads the Biochemistry scientific communications course and teaches nucleic acid chemistry and advanced crystallography.

“I think it is fitting that Martin is receiving this recognition,” Cortez said in his announcement. “He exemplifies so many of the same scholarly qualities as Richard.”

The Richard Armstrong Professorship is named for the late Dr. Richard Armstrong, Professor of Biochemistry and Chemistry at �Ӱ�ԭ�� and the Foreign Adjunct Professor at the Karolinska Institute in Stockholm, Sweden. Dr. Armstrong was a highly valued member of the Biochemistry department. His research focused on how enzymes detoxify foreign molecules through a multipronged chemical, structural, and molecular approach. As an editor of the journal Biochemistry, Armstrong fostered the dissemination of scientific knowledge. His work as a teacher, scholar, and advisor were instrumental in expertly guiding students through the rigors of Chemistry and Biochemistry. He emphasized fundamentals through his numerous lectures and selflessly served the Biochemistry community through teaching, committee membership, grant reviews, and participation in professional societies.