Predicting small molecule binding pockets on diacylglycerol kinases using chemoproteomics and AlphaFold

About this article

Diacylglycerol (DAG) lipids are important secondary messenger for cell signalling and cellular levels can be controlled through phosphorylation mediated by DAG kinases (DGK). Small molecule inhibitors of individual DGK proteins would be valuable tools to investigate DAG signalling but have been difficult to develop because of limited information on binding pockets available for targeting in cells.

An integrated chemical proteomics and AlphaFold strategy can predict unexpected binding regions for covalent inhibitor development.

 

Read the full article here.

 

 

About RSC Chemical Biology

Led by Hiroaki Suga (University of Tokyo), RSC Chemical Biology is dedicated to publishing and disseminating the most exceptionally significant, breakthrough findings of interest to the chemical biology community. All submissions are handled by our experienced and internationally recognised Associate Editors. For more information on the journal, please visit the journal homepage.

As a gold open access journal, there are no barriers to accessing content and your research article will reach an international audience. Please note that the article processing charges are waived until mid-2022, so the journal is currently free to publish in.

RSC Chemical Biology is now indexed in the Directory of Open Access Journals (DOAJ), PubMed Central, Scopus and Web of Science: Emerging Sources Citation Index.  Find out more about the journal and submit your work at rsc.li/rsc-chembio

 

RSC Chemical Biology

Royal Society of Chemistry

www.rsc.org

 

 

RSC Chemical Biology Webinar: Outstanding Paper Award Winner 2022

Join us to celebrate the Outstanding Paper Award winners of 2022!

The team at RSC Chemical Biology are delighted to invite you to our upcoming webinar to celebrate the winner of our Outstanding Paper Award from 2022. The winner is Professor Craig Crews, of Yale University, for their paper “OligoTRAFTACs: A generalizable method for transcription factor degradation”.

 

 

 

The webinar, scheduled to last for one hour, will feature a presentation from the group of Professor Craig Crews discussing their work, and this will be followed by a presentation from Professor Michelle Arkin, an Editorial Board Member for RSC Chemical Biology, highlighting some ongoing work in her group at the University of California, San Francisco.

This event is being held online through Zoom and is completely free to attend. It will be held on Tuesday 21st November at 17:00 GMT. You can find more information on our Event Page and can register for the event here.

We look forward to seeing you at the webinar!

 

 

The multivalent G-quadruplex (G4)-ligands MultiTASQs allow for versatile click chemistry-based investigations

About this article

G-quadruplexes (or G4s) are four-stranded DNA and RNA structures that fold from guanine (G)-rich sequences. G4 are suspected to play key biological roles in human cells and diseases. Small molecules that selectively target G4s (or G4-ligands) can thus be used as modulators to gain insights into the cell circuitry where G4s are involved. While hundreds of G4-ligands have been designed, synthesized and used, most if not all of them are flat aromatic molecules prone to interact with the duplex-DNA (the major form of DNA within the nucleus), which mechanically decreases their specificity for G4s.

We have developed a brand new molecular design, following a biomimetic approach that hinges on the observation that G4s are stable secondary structures owing to the ability of Gs to self-associate to form G-quartets, and then of G-quartets to self-stack to form the columnar core of G4s. Therefore, using a synthetic G-quartet as a G4-ligand represents a unique example of biomimetic recognition of G4s, relying on a like-likes-like approach, which is the surest pledge for a very high G4-selectivity.

In this article, we report on the design, synthesis and use of synthetic G-quartet-based ligands, also referred to as TASQs (for template-assembled synthetic G-quartets). These TASQs are the latest prototypes of TASQs, being multivalent TASQs (that is why we refer to them as MultiTASQs) able to be functionalized in situ by click chemistry (both CuAAC and SPAAC) for optical imaging and affinity precipitation purposes. These bioorthogonal investigations thus provides unique information about G4 biology.

Click on the infographic to read the full paper!

G-quadruplexes (or G4s) are four-stranded DNA and RNA structures that fold from guanine (G)-rich sequences. G4 are suspected to play key biological roles in human cells and diseases. Small molecules that selectively target G4s (or G4-ligands) can thus be used as modulators to gain insights into the cell circuitry where G4s are involved. While hundreds of G4-ligands have been designed, synthesized and used, most if not all of them are flat aromatic molecules prone to interact with the duplex-DNA (the major form of DNA within the nucleus), which mechanically decreases their specificity for G4s.

 

About RSC Chemical Biology

Led by Hiroaki Suga (University of Tokyo), RSC Chemical Biology is dedicated to publishing and disseminating the most exceptionally significant, breakthrough findings of interest to the chemical biology community. All submissions are handled by our experienced and internationally recognised Associate Editors. For more information on the journal, please visit the journal homepage.

As a gold open access journal, there are no barriers to accessing content and your research article will reach an international audience. Please note that the article processing charges are waived until mid-2022, so the journal is currently free to publish in.

RSC Chemical Biology is now indexed in the Directory of Open Access Journals (DOAJ), PubMed Central, Scopus and Web of Science: Emerging Sources Citation Index.  Find out more about the journal and submit your work at rsc.li/rsc-chembio

 

RSC Chemical Biology

Royal Society of Chemistry

www.rsc.org

 

 

Professor Christopher J. Chang recieves the ACS Alfred Bader Award

We’re pleased to share that Professor Christopher J. Chang, Advisory Board member for RSC Chemical Biology, is the recipient of the 2024 Alfred Bader Award in Bioinorganic or Bioorganic Chemistry. Congratulations Chris! You can read more about Chris’ award, and Professor Michelle Chang’s, in UC Berkeley’s announcement; and find out about all of the 2024 ACS National Award winners at their web page,

New themed collection on ‘Chemical Proteomics’

A slide summarising the information in this blog post, with images of the two Guest Editors

We’re pleased to announce that a new themed collection from RSC Chemical Biology on Chemical Proteomics has now been published online.

Read the collection

This collection, Guest Edited by Dr Keriann Backus (UCLA, USA) and Dr Stephan Hacker (Leiden University, Netherlands), highlights work on applications of chemoproteomics to study the targets and off-targets of covalent and non-covalent inhibitors, to study the reactivity of amino acids in the proteome, to develop new reactive groups for photocrosslinkers, covalent inhibitors and protein labeling as well as to study post-translational modifications and cofactor binding proteome-wide.

A listing of the articles has been provided below. All articles in RSC Chemical Biology are open access and free to read.

Perspective

Finding a vocation for validation: taking proteomics beyond association and location
Marcus J. C. Long, Jinmin Liu and Yimon Aye
RSC. Chem. Biol., 2023, 3, 110–120, DOI: 10.1039/D2CB00214K

Communications

Quantitative profiling of PTM stoichiometry by resolvable mass tags
Ying Chen, Baiyi Quan, Yuanpei Li, Yuan Liu, Wei Qin and Chu Wang
RSC. Chem. Biol., 2023, 3, 1320–1324, DOI: 10.1039/D2CB00179A

Chemoproteomic mapping of human milk oligosaccharide (HMO) interactions in cells
Abdullah A. Hassan, Jacob M. Wozniak, Zak Vilen, Weichao Li, Appaso Jadhav, Christopher G. Parker and Mia L. Huang
RSC. Chem. Biol., 2023, 3, 1369–1374, DOI: 10.1039/D2CB00176D

Papers

The covalent reactivity of functionalized 5-hydroxy-butyrolactams is the basis for targeting of fatty acid binding protein 5 (FABP5) by the neurotrophic agent MT-21
Esben B. Svenningsen, Rasmus N. Ottosen, Katrine H. Jørgensen, Marija Nisavic, Camilla K. Larsen, Bente K. Hansen, Yong Wang, Kresten Lindorff-Larsen, Thomas Tørring, Stephan M. Hacker, Johan Palmfeldt and Thomas B. Poulsen
RSC. Chem. Biol., 2023, 3, 1216–1229, DOI: 10.1039/D2CB00161F

A peptide-crosslinking approach identifies HSPA8 and PFKL as selective interactors of an actin-derived peptide containing reduced and oxidized methionine
Aaron Maurais and Eranthie Weerapana
RSC. Chem. Biol., 2023, 3, 1282–1289, DOI: 10.1039/D2CB00183G

Chemical proteomic analysis of bile acid-protein targets in Enterococcus faecium
Xinglin Yang, Xiaohui Zhao, Victor Chen and Howard C. Hang
RSC. Chem. Biol., 2023, 3, 1397–1402, DOI: 10.1039/D2CB00178K

Photoreactive bioorthogonal lipid probes and their applications in mammalian biology
Karthik Shanbhag, Kavita Sharma and Siddhesh S. Kamat
RSC. Chem. Biol., 2023, 3, 37–46, DOI: 10.1039/D2CB00174H

Predicting small molecule binding pockets on diacylglycerol kinases using chemoproteomics and AlphaFold
Roberto Mendez, Minhaj Shaikh, Michael C. Lemke, Kun Yuan, Adam H. Libby, Dina L. Bai, Mark M. Ross, Thurl E. Harris and Ku-Lung Hsu
RSC. Chem. Biol., 2023, 3, 422–430, DOI: 10.1039/D3CB00057E

We hope you enjoy this new themed collection from RSC Chemical Biology.

A fluorescent photoaffinity probe for formyl peptide receptor 1 labelling in living cells

About this article

The paper explores developing a chemical tool to label formyl peptide receptor 1 (FPR1) in cells. FPR1 is a sensor in the human innate immune system, which is our body’s ancient first-line response system to detect pathogens. FPR1 is found in our immune cells; it helps these cells move towards sites of infection by sensing peptides released from bacteria.

However, the role of FPR1 is not so simple. FPR1 has been reported in other cells, such as those lining our mucous membranes (gut, lungs etc.), where it presumably comes into contact with many of our friendly bacteria without causing widespread immune activation. This family of proteins (FPRs1-3) can recognise very different molecules, and how this occurs is only beginning to be explored. FPRs can also cause and suppress inflammation and have been linked to numerous diseases (cancer, autoimmune disease). However, it’s unclear how this occurs and how we might modulate it to treat diseases.

In this paper, we designed a tool to label or tag FPR1 with a dye so we can see this sensor on the surface of cells. Our tool also allows us to detect inhibitors that bind FPR1. A key feature of it, is that it permanently labels FPR1. We expect it will be useful to understand the fundamentals of FPR1 biology and explore how we can treat diseases through molecules that activate or repress this protein.

Image of the article

About RSC Chemical Biology

Led by Hiroaki Suga (University of Tokyo), RSC Chemical Biology is dedicated to publishing and disseminating the most exceptionally significant, breakthrough findings of interest to the chemical biology community. All submissions are handled by our experienced and internationally recognised Associate Editors. For more information on the journal, please visit the journal homepage.

As a gold open access journal, there are no barriers to accessing content and your research article will reach an international audience. Please note that the article processing charges are waived until mid-2022, so the journal is currently free to publish in.

RSC Chemical Biology is now indexed in the Directory of Open Access Journals (DOAJ), PubMed Central, Scopus and Web of Science: Emerging Sources Citation Index.  Find out more about the journal and submit your work at rsc.li/rsc-chembio

 

RSC Chemical Biology

Royal Society of Chemistry

www.rsc.org

 

 

Celebrating Excellence in Chemical Biology: RSC Chemical Biology Outstanding Paper Award 2022

We are delighted to announce our annual RSC Chemical Biology Outstanding Paper 2022 Award, to recognize some of the outstanding work published in the journal, as well as the authors behind those articles. Selected by our Editorial Board, the winning paper was chosen from a shortlist based on the science presented, and also the potential future impact of the research.

We are thrilled to reveal that the award for 2022 goes to

“OligoTRAFTACs: A generalizable method for transcription factor degradation”

Authors:  Kusal T. G. Samarasinghe, Elvira An, Miriam A. Genuth, Ling Chu, Scott A. Holley, and Craig M. Crews.

RSC Chem. Biol., 2022,3, 1144-1153
DOI 10.1039/D2CB00138A

 

This paper represents a significant leap forward in the field of chemical biology. It introduces a novel method, OligoTRAFTACs, which provides an approach for targeted transcription factor degradation. We reached out to the winning team, and they shared their thoughts on receiving this prestigious award. In their words, “We are honoured and pleased to receive the 2022 RSC Chemical Biology Outstanding Paper Award. We thank the editorial board members for recognizing our work on developing oligoTRAFTACs for targeted transcription factor degradation. Targeted protein degradation has been widely explored in academia and industry, and many degraders are already found their way to the clinic. We believe that progressive innovation of proximity-inducing modalities will contribute to expanding the targeted protein degradation and beyond. This recognition highlights the importance of such developments, and it will undoubtedly impel the research community to further advance the chemical biology field.”

Furthermore, we are excited to announce that the winning team will be presenting their research in a webinar series scheduled for October, with the date to be defined. This will be a unique opportunity to delve deeper into their ground-breaking work and engage with the authors directly.

Meet the authors

 

Let’s take a moment to get to know the authors behind this exceptional paper:

  • Dr. Craig M. Crews is the John C. Malone Professor of Molecular, Cellular and Developmental Biology at Yale University. With a rich academic and biotech background, Dr. Crews has been a pioneer in using small molecules to control intracellular protein levels. His contributions have led to the development of innovative therapies, including the FDA-approved drug Kyprolis™ for the treatment of multiple myeloma. Dr. Crews’ commitment to advancing the field of chemical biology has earned him numerous awards and honors, including the Connecticut Medal of Technology in 2022.
  • Dr. Scott A. Holley, a Professor and Chair of the Department of Molecular, Cellular and Developmental Biology, specializes in systems developmental biology, biophysics, and biomechanics. His research focuses on early spinal column development in zebrafish, shedding light on the fundamental processes that shape vertebrate embryos.
  • Dr. Ling Chu, born and raised in China, has a diverse academic journey, from chemistry to chemical biology. After completing his Ph.D. at the Scripps Research Institute, he transitioned to chemical biology research at Yale School of Medicine, where he developed innovative tools for live-cell super-resolution imaging. Dr. Chu’s work has bridged the gap between chemistry and biology.
  • Miriam A. Genuth holds a BA from the University of Chicago and a Ph.D. from the University of California, San Francisco. Her research journey has led her to study chick cranial neural crest cell migration and zebrafish body elongation in the Holley lab at Yale, contributing to our understanding of developmental biology.
  • Elvira An, a graduate candidate in the Department of Pharmacology at Yale University, brings her background in mathematics and post-baccalaureate research experience to the lab of Craig Crews. Her research focuses on unraveling the mechanisms of chemically induced cell fate changes, a critical area in chemical biology.
  • Kusal T. G. Samarasinghe’s academic journey spans from Sri Lanka to the United States, culminating in his pivotal role in the development of OligoTRAFTACs. His work targets hard-to-drug transcription factors, expanding the druggable space within targeted protein degradation and pushing the boundaries of what’s possible in this field.

The RSC Chemical Biology Outstanding Paper 2022 Award not only celebrates the accomplishments of these exceptional researchers but also highlights the transformative potential of their work. We eagerly anticipate the impact of OligoTRAFTACs on the future of chemical biology and look forward to the insights that will be shared during the upcoming webinar series.

Congratulations to the winning team, and thank you for your invaluable contributions to the field of chemical biology!

 

SREBP activation contributes to fatty acid accumulations in necroptosis

About this article:

Necroptosis is a type of programmed cell death that is accompanied by extensive inflammatory activity. Previously, it has been shown that lipids accumulate in this process, and the accumulation exacerbates the membrane permeability and cell death in necroptosis.

However, the mechanisms that result in the accumulation of these lipids are unknown.

In this work, the authors used a global transcriptomics approach. They investigated the changes in the expression of proteins involved in lipid biosynthesis and transport to identify upstream mechanisms that cause lipid accumulation in necroptosis. Such a transcriptomics approach combined with further targeted experiments revealed the activation of a key regulatory mechanism of lipid production, namely sterol regulatory element binding proteins.

The authors showed that modulating the activation of sterol regulatory element binding proteins impacts necroptotic phenotype, demonstrating the functional role of these proteins in the accumulation of toxic lipids in necroptosis. Moreover, these results provide insights into mechanisms that regulate lipid production in cell death.

 

Infographic of SREBP activation contributes to fatty acid accumulations in necroptosis

About RSC Chemical Biology

Led by Hiroaki Suga (University of Tokyo), RSC Chemical Biology is dedicated to publishing and disseminating the most exceptionally significant, breakthrough findings of interest to the chemical biology community. All submissions are handled by our experienced and internationally recognised Associate Editors. For more information on the journal, please visit the journal homepage.

As a gold open access journal, there are no barriers to accessing content and your research article will reach an international audience. Please note that the article processing charges are waived until mid-2022, so the journal is currently free to publish in.

RSC Chemical Biology is now indexed in the Directory of Open Access Journals (DOAJ), PubMed Central, Scopus and Web of Science: Emerging Sources Citation Index.  Find out more about the journal and submit your work at rsc.li/rsc-chembio

 

RSC Chemical Biology

Royal Society of Chemistry

www.rsc.org

 

 

Professor Laura Kiessling joins the Advisory Board

Welcome Prof Kiessling to RSC Chemical Biology!

 

 

We are delighted to welcome Prof Kiessling to the Advisory Board of RSC Chemical Biology.

Professor Kiessling received an Sc.B. degree in chemistry at MIT, where she performed undergraduate research in organic synthesis with Professor Bill Roush. She received a Ph.D. degree in chemistry at Yale University for her research with Stuart L. Schreiber. She was an American Cancer Society postdoctoral fellow with Peter B. Dervan at California Institute of Technology. She then joined the faculty at the University of Wisconsin–Madison, where she became the Steenbock Professor of Chemistry, the Laurens Anderson Professor of Biochemistry, and the Director of the Keck Center for Chemical Genomics. In 2017, she returned to MIT as the Novartis Professor of Chemistry.

Professor Kiessling is a member of the American Academy of Arts & Sciences, the American Academy of Microbiology, the American Philosophical Society, and National Academy of Sciences. She is the founding Editor-In-Chief of the journal ACS Chemical Biology . She is an author of over 140 peer-reviewed journal articles, and an inventor on more than 28 US patents. She has advised approximately 100 graduate students and postdoctorates. Alumni from her research group are contributing through their positions as faculty members of distinguished research universities, medical schools, and colleges and as research scientists at innovative start-up companies, leading corporations, and government laboratories.

 

About RSC Chemical Biology

Led by Hiroaki Suga (University of Tokyo), RSC Chemical Biology is dedicated to publishing and disseminating the most exceptionally significant, breakthrough findings of interest to the chemical biology community. All submissions are handled by our experienced and internationally recognised Associate Editors. For more information on the journal, please visit the journal homepage.

As a gold open access journal, there are no barriers to accessing content and your research article will reach an international audience. Please note that the article processing charges are waived until mid-2022, so the journal is currently free to publish in.

RSC Chemical Biology is now indexed in the Directory of Open Access Journals (DOAJ), PubMed Central, Scopus and Web of Science: Emerging Sources Citation Index.  Find out more about the journal and submit your work at rsc.li/rsc-chembio

 

RSC Chemical Biology

Royal Society of Chemistry

www.rsc.org

 

 

A mechanistic study on the cellular uptake, intracellular trafficking, and antisense gene regulation of bottlebrush polymer-conjugated oligonucleotides

A research infographic summarising the linked article.

Read the full article here.

RSC Chemical Biology is now indexed in the Directory of Open Access Journals (DOAJ), PubMed Central, Scopus and Web of Science: Emerging Sources Citation Index.  Find out more about the journal and submit your work at rsc.li/rsc-chembio

RSC Chemical Biology

Royal Society of Chemistry

www.rsc.org