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’s 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.

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PROteolysis TArgeting Chimeras, known as PROTACs, are a recently developed group of therapeutics that utilize the ubiquitin-proteasome system to target and degrade disease associated proteins by recruiting E3 ligase. Of the many different E3 ligases found in human cells, over 600 are known to be expressed and only a few are used with PROTACs.

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 Vanderbilt 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.

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A group of Vanderbilt 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 Vanderbilt 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 .

Heme is vital for life. It is needed for oxygen transport, drug detoxification, and many other biological functions. Regulation is key, too much or too little heme can cause a host of problems in the body. Aminolevulinic acid synthase (ALAS) is heme’s rate-limiting enzyme that functions by the condensation of glycine and succinyl-CoA to produce aminolevulinic acid. Two isoforms are found in humans, denoted as ALAS1 and ALAS2, the latter of which controls 85 to 90% of heme synthesis. Most disease-causing mutations are found in this enzyme and recent studies suggest that ALAS2 is more widely expressed than previously thought.

Dr. Iva Chitrakar, a postdoc in the lab of Dr. Breann Brown, states that this underscores the critical need to understand ALAS2’s 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 Vanderbilt as an assistant professor in 1995 and became professor of biochemistry in 2005.

Dr. Egli’s 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 ��һ��ݶ� 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’s 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 ��һ��ݶ� 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.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor transcription factor which regulates the expression of genes involved in differentiation, metabolism, adipogenesis, and insulin sensitization. PPARγ consists of an N-terminal disordered activation domain (NTD), a central DNA-binding domain (DBD), and a C-terminal ligand-binding domain (LBD). The activation and repression of PPARγ is mediated by the recruitment of coactivator and corepressor complexes, whose binding to PPARγ is modulated further by agonist binding. This complex regulatory cycle is necessary for proper cell function, as evidenced by the fact that aberrant PPARγ signaling occurs in luminal muscle-invasive bladder cancer. Therefore, the development of pharmaceuticals which target PPARγ-mediated transcription is an area of popular research.

In 2002, a covalent PPARγ antagonist, T0070907, was developed which effectively blocked agonist binding and reduced PPARγ-mediated transcription. However, T0070907 was not equally effective against all PPARγ ligands. Furthermore, T0070907 was shown to act not solely as an antagonist, but also as an inverse agonist, which stabilized the corepressor-bound repressive conformation of PPARγ over the coactivator-bound active conformation. Based on this knowledge, pharmaceutical companies have pivoted to designing new inverse agonists with the goal of suppressing PPARγ-mediated transcription to an even greater degree.

In this study led by Zane Laughlin, a former postdoctoral fellow in the , the researchers report the cellular, biochemical, and structural profiling of FX-909, a new PPARγ inverse agonist from Flare Therapeutics.

To assess the effect of various ligands on PPARγ-mediated transcription, a HEK293T cell transcriptional reporter assay was used which linked a PPAR-binding DNA response element to the firefly luciferase gene. FX-909, along with other covalent inverse agonists, resulted in a concentration-dependent decrease in PPARγ transcription with similar potencies. GW9662, an antagonist, resulted in no change in activity, and rosiglitazone, an agonist, led to an increase in transcription.

The researchers next sought to determine the effect of ligand-PPARγ binding on the association of different coregulator peptides using time-resolved fluorescence energy transfer. FX-909 demonstrated a concentration-dependent increase in corepressor peptide interaction, and a decrease in coactivator interaction with similar potencies to the other covalent inverse agonists. However, FX-909 exhibited a higher TR-FRET efficacy in recruiting the corepressor peptide as compared to its parent compound, T0070907. This difference was further enforced by fluorescence polarization assays which demonstrated a stronger binding affinity between PPARγ LBD and the corepressor peptide in the presence of FX-909 as opposed to T0070907.

The researchers then sought to gain a more complete understanding of the structural changes enacted by FX-909 binding and therefore determined a 2.1 Å crystal structure of the PPARγ LBD bound to FX-909 and a corepressor peptide to. In the structure, the PPARγ LBD adopted a transcriptionally repressive conformation, in which helix12 was occluded, leaving a coregulator binding surface open for the corepressor peptide to bind. However, the binding pose of FX-909 in the ligand-binding pocket and the corepressor peptide on the coregulator binding surface were very similar to crystal structures of the PPARγ LBD bound to T0070907, prompting the use of NMR to fully understand the impact of FX-909 on PPARγ structure. When T0070907 is bound to the PPARγ LBD, the population is split roughly equally between active and repressive conformations, but when FX-909 is bound, the population is highly skewed towards the repressive conformation.

Taken together, these data demonstrate that the increased efficacy of FX-909 is a result of the compound’s ability to stabilize the repressive conformation, increasing corepressor binding, and leading to a decreased level of PPARγ-mediated transcription. This represents the first mechanistic characterization of FX-909, which is currently in clinical trials as a cancer drug, and provides a basis for future drug modulations of PPARγ activity.

Check out the for the full story!

Congratulations to Kate Clowes Moster, of the , on being named the 2026 recipient of the Dr. Anne Karpay Award in Structural Biology. “I’m really honored to be selected for the Karpay Award,” Clowes Moster said.

Kate began her scientific journey in West Virginia, where she grew up fascinated with nature and animals. This progressed into an interest in science and research after attending several science-based summer camps during her middle and high school years. Kate eventually found her way to the University of Kentucky to earn her Bachelor of Science degree in chemistry.

As an undergraduate, Kate honed her research skills by performing research in the lab of Dr. Luke Bradley, participating in an REU program at Miami University in the lab of Dr. Gary Lorigan and contributing to an NSF SURF program at Scripps Florida in the lab of Dr. Scott Hansen.

Kate is a graduate student in the Biochemistry Graduate Program and a member of the Sanders lab since 2020. Her research focuses on the potassium channel KCNQ1 and mutations that cause a cardiac disorder called type 1 long QT syndrome (LQT1). Sanders lab researchers have determined that mistrafficking is a common cause of KCNQ1 dysfunction in LQT1. Kate’s effort to search for small molecules that might remedy this mistrafficking provides an early foundation for possible drug discovery efforts to treat LQT1 and related cardiac disorders.

“Kate is a versatile scientist who is exceptionally devoted to rigor and reproducibility,” Professor Sanders said. “She lives out her belief in the importance of service and is always willing to step up and help out!”

Throughout her scientific career, Kate has collaborated with the Jens Meiler lab at Vanderbilt and the Alfred George lab at Northwestern University. She maintains a close working relationship with the team at the Vanderbilt High-throughput Screening Core as well as the VICB Molecular Design and Synthesis Core and the VUMC Flow Cytometry Shared Resource.

When she’s not working on her research, Kate enjoys eating at new Nashville-area restaurants with her husband and friends in tow and cooking tasty meals at home. “I love to cook, and I love to eat!” exclaimed Clowes Moster. She prefers restaurants and breweries with fun events, such as trivia nights or pop-up themes.

Kate presents Avoiding traffic jams: Correcting KCNQ1 mistrafficking and navigating grad school on Tuesday, January 20, 2026, as part of the MBTP/CSB Seminar Series. The seminar begins at 12:20pm in 1220 MRB3 with the award presentation and reception to follow.

“Anne Karpay has such a special legacy throughout the CSB,” Clowes Moster said. “It’s a great honor to be selected for this award in her memory.”

The Dr. Anne Karpay Award in Structural Biology was established in 2010 to honor the memory of Dr. Anne Karpay, who died after a four-year battle with breast cancer. It is funded entirely by donations to an endowment managed through the Development Office of the ��һ��ݶ� School of Medicine. Donate to the endowment fund.

No one can argue that the development of AlphaFold2 (AF2) has been one of the greatest achievements in the realm of protein structure prediction. However, AF2 has been plagued by two major limitations: (1) The quality of the predicted models depends on the quality of the multiple sequence alignment (MSA) input and (2) The assumption that this input sequence only folds into one conformation. It is known that proteins are dynamic models that have multiple folding states in order to carry out their biological function.

Although these limitations exist, there has always been a desire to refine and guide AF2 with experimental data, especially in the context of incorporating the protein energy landscape. While there have been methods to “hack” AF2, performance of the algorithm has been variable. Some tools, AlphaLink which uses cross-linking mass spectrometry data, have been developed and demonstrate the ability to tune AF2 predictions with collected data. This proves that AF2 has the flexibility to accept these inputs, but predictions of multiple conformations have yet to be addressed. This is largely due to the fact that data collected from probe-based spectroscopic techniques, such as Double Electron Electron Resonance (DEER) spectroscopy, present a unique challenge due to the probe’s flexible movement, or rotameric freedom, relative to the protein backbone.

To tackle this issue, members of the and the set out to develop an AF2 tool that can incorporate DEER distributions and provide a blueprint for other spatial constraints.

Dubbed “DEERFold,” this new tool was created by fine-tuning AF2 within the OpenFold framework to interpret and integrate spin-label distance distributions from DEER spectroscopy directly into the network architecture. While AF2 is limited by its training on the Protein Data Bank (PDB) and typically yields a single structure, DEERFold can predict alternative, heterogeneous conformational ensembles when distance constraints are applied. A systematic evaluation showed that incorporating either experimental or simulated DEER constraints successfully drives the model toward the desired conformation. Importantly, the authors found that the content of the constraints, rather than their exact shape, is the main factor in improving the quality of the predictions. These findings highlight DEERFold’s utility in modeling conformational changes, even when initial or target experimental structures are not known.

DEERFold’s success shows that AF2 can be molded to include many other forms of experimental data, such as nuclear magnetic resonance (NMR), fluorescence resonance energy transfer (FRET), hydrogen-deuterium exchange (HDX), and cross-link mass spectrometry (XL-MS).

The authors hope that DEERFold could be used as a platform for this inclusion and bring in extremely valuable data to enhance protein structure prediction.

Read the full paper in .