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Targeted covalent inhibitors have regained widespread attention in drug discovery and have emerged as powerful tools for basic biomedical research. Fueled by considerable improvements in mass spectrometry sensitivity and sample processing, chemoproteomic strategies have revealed thousands of proteins that can be covalently modified by reactive small molecules. Fragment-based drug discovery, which has traditionally been used in a target-centric fashion, is now being deployed on a proteome-wide scale thereby expanding its utility to both the discovery of novel covalent ligands and their cognate protein targets. This powerful approach is allowing ‘high-throughput’ serendipitous discovery of cryptic pockets leading to the identification of pharmacological modulators of proteins previously viewed as “undruggable”. The reactive fragment toolkit has been enabled by recent advances in the development of new chemistries that target residues other than cysteine including lysine and tyrosine. Here, we review the emerging area of covalent fragment-based ligand discovery, which integrates the benefits of covalent targeting and fragment-based medicinal chemistry. We discuss how the two strategies synergize to facilitate the efficient discovery of new pharmacological modulators of established and new therapeutic target proteins., Covalent fragment-based ligand discovery greatly facilitates the discovery of useful fragments for drug discovery and helps unveil chemical-tractable biological targets in native biological systems.

Introductory discussion of Targeted Protein Degradation and Proximity-Based Pharmacology - as presented to editors of Nature Research Journals on September-28-2021.

Correction for ‘Fragment-based covalent ligand discovery’ by Wenchao Lu et al., RSC Chem. Biol., 2021, DOI: 10.1039/d0cb00222d.

Thanks to the organizers of the 3rd Annual Chemical Biology in the Hub event I was given an opportunity to open the meeting. To get us started, I thought it would be valuable to enlist the help of an auditorium full of chemical biologists to brainstorming about where we wanted our field to go next and what we wanted chemical biology to be. Why is this an important conversation to have at this point? In my view, chemical biology is still a youngish field. We have reached a stage of adolescence when we can do a great many things, we are energetic, we are excited, we continue to test the limits and we are definitely ready to dive into things that others may view as intellectually potentially dangerous! Our field is growing, thanks to many early career scientists who have been joining us. With this comes a growing responsibility to create a community that welcomes others and ensures their mentoring and wellbeing. Additionally, we have to be ready to be vocal and advocate for what it is that chemical biology can do and why it matters, and what our culture and standards are. And that’s why I decided to put this question of what it is that we want to be when we grow up in front of everyone in the audience at the Third Annual "Chemical Biology in the HUB" symposium.

Some of the most widely used drugs, such as aspirin and penicillin, are covalent drugs. Covalent binding can improve potency, selectivity, and duration of the effects, but the intrinsic reactivity represents a potential liability and may result in idiosyncratic toxicity. For decades, the cons were believed to outweigh the pros, and covalent targeting was deprioritized in drug discovery. Recently, several covalent inhibitors have been approved for cancer treatment, thus rebooting the field. In this review, we briefly reflect on the history of selective covalent targeting, and provide a comprehensive overview of emerging developments from a chemical biology stand-point. Our discussion will reflect on efforts to validate irreversible covalent ligands, expand the scope of targets, and discover new ligands and warheads. We conclude with a brief commentary of remaining limitations and emerging opportunities in selective covalent targeting.

Summary KRAS is the most frequently mutated oncogene found in pancreatic, colorectal, and lung cancers. Although it has been challenging to identify targeted therapies for cancers harboring KRAS mutations, KRASG12C can be targeted by small-molecule inhibitors that form covalent bonds with cysteine 12 (C12). Here, we designed a library of C12-directed covalent degrader molecules (PROTACs) and subjected them to a rigorous evaluation process to rapidly identify a lead compound. Our lead degrader successfully engaged CRBN in cells, bound KRASG12C in vitro, induced CRBN/KRASG12C dimerization, and degraded GFP-KRASG12C in reporter cells in a CRBN-dependent manner. However, it failed to degrade endogenous KRASG12C in pancreatic and lung cancer cells. Our data suggest that inability of the lead degrader to effectively poly-ubiquitinate endogenous KRASG12C underlies the lack of activity. We discuss challenges for achieving targeted KRASG12C degradation and proposed several possible solutions which may lead to efficient degradation of endogenous KRASG12C.

Every month the editors of Cell Chemical Biology bring you highlights of the most recent chemical biology literature. Our September 2016 selection includes the discovery of PZM21, a μOR biased agonist with minimal side effects, and the role of cholesterol in Hedgehog signaling pathway.

Table of Content Wish List“An Atomic Resolution Map of a Working Cell” (Bridget Carragher)“A Universal Method for Compound Target Identification” (James K. Chen)“A Lego Kit of Biosynthetic Modules for Secondary Metabolite Production” (James K. Chen)“Quantitative Sequencing of Carbohydrate Modifications on Proteins” (James K. Chen)“Evolution of Smart Materials” (Jason Chin)“Mars Needs Histones” (Andrea G. Cochran)“Metabolomic Engineering: A Systems Biology Application of Large Scale Chemical Biology” (Craig M. Crews)“Antibiotic Resistance Conquered” (Zixin Deng)“Single Microbe as a Drug Bank: Opening the Treasure Hidden in the Crypts” (Zixin Deng)“Rapid Experimental Evolution of New Antibiotics” (Elke Dittmann)“A Synthetic Self-Replicating Proto-Cell” (Michael Famulok)“Synthesis of a Complete, Universal T Cell Genome Optimized for Engineering” (Michael Fischbach)“High Coverage Proteomics Dataset Collected Using a Smart Phone” (Jason Gestwicki)“Combined Genomic and Metabolic Profiling of Tumors Leads to the Development of an Efficient Personalized Targeted Therapeutic Approach” (Eyal Gottlieb)“Chemical Mind Biology” (Masatoshi Hagiwara)“Mirror Image Protein Synthesis” (Michael C. Jewett)“Incipient Speciation in a Synthetic Microbial Ecosystem” (Gerald F. Joyce)“Continuous Monitoring of Single-Cell RNA Expression during Hepatic Regeneration” (Gerald F. Joyce)“Discovery of Compounds that Prevent Neurodegeneration” (Thomas J. Kodadek)“Small Molecule PCR” (Luke Lavis)“First Fully Synthetic Living Cell” (Edward Lemke)“Ten Color Optogenetic Control of a Flying Drosophila” (Edward Lemke)“Small Molecule Cocktail Alters Cell Fate between Growth and Differentiation” (Jun Liu)“Metabolomic Engineering: A Systems Biology Application of Large Scale Chemical Biology” (Wen Liu)“Biology from Omic Landscape to Molecular Details” (Minkui Luo)“Precision Medicine: Localized Restoration of Chemical Imbalance in Disease Brain States” (Milka Kostic)“Single Cell Proteomes Reveal Disease and Drug Biomarkers in Humans” (Timothy J. Mitchison)“Nanomolar Affinity, High Selectivity Binding Partners for Any Biomolecule in 1 Day for under $100” (Timothy J. Mitchison)“Error-free Mutation Repair in Human Eggs (or .…Neurons)” (Timothy J. Mitchison)“Accurate Prediction of Protein Sub-cellular Localization across a Newly Sequenced Genome” (Timothy J. Mitchison)“On-Chip Measurement of 1000 Urine Biomolecules Allows Accurate Diagnosis of Early Stage Cancers” (Timothy J. Mitchison)“New Probes for Non-invasive Imaging of Mycobacterium tuberculosis in Latently Infected Humans” (Valerie Mizrahi)“A 2 Week Cure for Tuberculosis” (Valerie Mizrahi)“Visualizing Metallation and Mismetallation of Proteins in Live Cells” (Elizabeth M. Nolan)“Small Molecule Inhibitors of Muscle Atrophy and Memory Loss in the Aging Male” (Randall Peterson)“Polyketide Synthesis and Elaboration by a Remodeled Translation Apparatus” (Alanna Schepartz)“Reprogramming the Cellular Glycome Based on Rapid Glycan Sequencing and Synthesis” (Peter Seeberger)“Protein PCR” (Kevan Shokat)“De Novo Evolution of Entirely New Catalytic Function by Protein Enzymes” (Scott K. Silverman)“Biochemistry of First Living Isolate from Mars” (Brent Stockwell)“Rationally Designed Kampo Medicine” (Motonari Uesugi)“A Success Story on the Discovery and Development of Novel Antibiotics for the Clinical Treatment of Multi-Drug-Resistant Pathogens” (Tilmann Weber)“A Small-Molecule Ligand for Every Protein in the Proteome” (Eranthie Weerapana)“Highly Potent, Selective and Non-protein Binding Small Molecules Targeting RNA” (Herbert Waldmann)“Small Molecules as Big Players in Immuno-Oncology” (Herbert Wladmann)“Bioinformatic Tools to Extract More Information out of the Plethora of Primary Data” (Wolfgang Wohlleben)“Chemical Biology of the Gram-Negative Envelope; In Particular, How to Breach It with Small Molecules” (Gerard D. Wright)“Combinatorial Biosynthesis of Polyketides and Non-Ribosomal Peptides Comes True” (Wenjun Zhang)

Those of you who still browse the print issue of Structure might notice that this issue’s masthead looks different, and those reading our content online might notice changes to our Editorial Board page. Over the last few months, we have been working closely with our current Editorial Board members and others in the structural biology community on revising and expanding Structure’s Editorial Board. We are pleased to welcome a group of twenty-nine new board members and would like to use this editorial as an opportunity to introduce our expanded Editorial Board to you. We would also like to extend thanks to our current and retiring members for their continued support over the years.Structure is committed to considering any submission that addresses questions of high interest to the structural biology community, regardless of the method employed. In practical terms, this means that as structural biology continues to change and grow, so does our scope. As a consequence, over the last couple of years, our content has become more diverse and now includes reports that employ not only crystallography, electron microscopy (EM), and nuclear magnetic resonance (NMR) spectroscopy, the three techniques that form a core of structural biology efforts, but also depends on tools such as mass spectrometry (MS), small angle scattering (SAXS), various computational methods, single molecule studies, and integrative approaches. In addition to the increased diversity of methods, the kinds of questions that structural biologists ask have also expanded, and we publish findings that span broad interests in basic biology and biomedical science as well as biotechnology and translational research.In many ways, our expanded Editorial Board better reflects this diversification of structural biology. We are confident that our board members will continue to provide the Editors with valuable advice on challenging editorial decisions, on general editorial policy and standards, and on broader issues that affect advancement of structural biology. As active members of the structural biology community, our Editorial Board members are also our reviewers, authors, and readers, and we ask them to serve as ambassadors of the journal, as our eyes and ears, and to help keep Structure’s standards exceptional, our content timely and relevant, and our commitment to the community enduring.

Every month the editors of Cell Chemical Biology bring you highlights of the most recent chemical biology literature. Our November 2016 selection includes the discovery that cholesterol supply is a weak link in glioblastoma metabolism and the finding that nuclear hormone receptors are in the center of the complicated relationship we have with the hepatitis C virus.

Every month the editors of Cell Chemical Biology bring you highlights of the most recent chemical biology literature. Our October 2016 selection includes systematic structural, biochemical, and cellular characterization of B-RAF inhibitors; connecting bacterial transporters with their physiologically relevant ligands; and rewiring yeast metabolism for industrial scale production of isoprenoids.

From where I sit, the peer review process is not unlike the families described by Leo Tolstoy in his masterpiece Anna Karenina: “All happy families are alike; each unhappy family is unhappy in its own way.” We all know what the prevailing peer review process entails. A newly submitted manuscript is first subjected to editorial review and if deemed to satisfy editorial criteria in terms of scope and the significance of the findings, it is sent out for external review. External peer review usually involves several experts working on questions and systems that are similar or related to those discussed in the manuscript under consideration. These experts will read the work and provide editors and authors with a set of comments about the technical merit of the work and whether the insights obtained are likely to be viewed as important for the field. The editor will then evaluate the comments and reach a decision, usually in consultation with an editorial team and often in additional consultation with the reviewers.The goal of every editor is to publish scientific results that not only advance the science but are reliable, reproducible, and ready for follow up. In some cases, the reviewers have a unified positive view of a study, and the editors, authors, and reviewers become a part of one happy family. But there are also those cases in which this unity of opinions does not materialize, and the reviewers, editors, and authors find themselves at odds with each other. Based on my experience, every “unhappy” peer review outcome is indeed “unhappy in its own way.”As the editor, my focus is first and foremost on science and not on degrees of individual happiness. However, I do recognize and revere the fact that science is done and peer reviewed by passionate and driven people who invest huge amounts of blood, sweat, and tears into their own research and then more time, energy, and intellect in evaluating the research of others. So, when we started talking about re-launching Chemistry & Biology as Cell Chemical Biology and rethinking our scope and criteria for what it takes for a piece of scientific work to be a strong candidate for publication in the new journal, we also began to discuss how this change would affect our authors and reviewers. Because we wanted to strengthen the journal and make it more influential and engaging, very early on we realized that we couldn’t do it alone. Not only did we need to clearly communicate our revised standards and scope to our authors, we also wanted to enlist the help of our reviewers in making the process of putting Cell Chemical Biology on a new and exciting trajectory a true collaboration between us and the chemical biology community.Although the first issue of Cell Chemical Biology came out in January 2016, the outreach and reviewer and author engagement began around September 2015. We did this because we wanted our community to be aware of the plans to relaunch the journal, and because we were keen to gather feedback, suggestions, concerns, and expectations. We also wanted to let the authors who were submitting their work in the last few months of 2015 know that those papers were being evaluated with revised standards in mind and to ask the reviewers refereeing those manuscripts to apply our updated criteria.It became obvious that we had to be very clear on what we wanted our reviewers to keep in mind as they evaluated potential candidates for publication in Cell Chemical Biology. After a great deal of discussion, internal and external, we decided to frame our criteria in the form of the following questions that we hoped our reviewers would help us answer. (1) Is the paper technically solid and reported at the level at which other labs can use and reproduce the findings? (2) Is this paper among the top 10% of papers you reviewed over the last 1–2 years in this field? (3) Would you label it as “must read” for your lab's journal club or suggest it to colleagues and collaborators? (4) Do the reported findings change your view of the field? (5) Are you looking forward to seeing this work published? Finally, for Resource articles, we also started asking whether the authors present a new, innovative way to tackle important biological questions and provide compelling evidence that their approach will yield significant improvements over what is already out there.We made it clear that we don't expect specific answer, but that we hoped these questions would help reviewers frame their thinking and help them reset their bar. Many of our reviewers had been reviewing for Chemistry & Biology, and we wanted to make sure that they were on board with what we were trying to achieve with Cell Chemical Biology. We also wanted to extend our scope and emphasize the biological relevance of the work published in Cell Chemical Biology, which means that we have been enlisting help from many new reviewers, and these questions help them understand better what the journal is all about. Finally, chemical biology is a young field, with many early career researchers just stepping into it. We want to welcome them into the journal's family both as reviewers and authors, and we are sensitive that part of the career development needs of early career researchers revolve around how to navigate the peer review process and be a constructive reviewer.In addition to clarifying the criteria and prompting reviewers to think a bit differently about how to evaluate Cell Chemical Biology papers, we also wanted the entire peer review process to be more collaborative and open and more rewarding for our reviewers. Therefore, we decided to not only allow reviewers to see each other's comments once they've completed their assignment, but also to make our editorial decision letters open to the reviewers. This means that each reviewer receives notification of when the editorial decision is made as well as instructions on how to access comments from other reviewers and the editorial decision letter. However, we don’t stop there. In addition to thanking the reviewers for their efforts and advice, we also ask them for feedback. We ask them to let us know what their experience reviewing for Cell Chemical Biology was like and whether they thought our editorial and peer review process was fair, constructive, and clear. We ask our reviewers to let us know if there is anything that we can do to make reviewing easier and better.It’s been a year since we introduced some of these changes, and we are gratified by the response from the reviewers and the authors. As we push on to improve Cell Chemical Biology and to make a difference in the fascinating field of chemical biology, we continue to consider Cell Chemical Biology an ongoing collaboration among us, our authors, and our reviewers. Although we can’t publish every paper that is submitted to us, we can and do work relentlessly to create a more open and friendly environment in which scientists who we interact with feel respected and engaged, regardless of whether the final publishing decision is a positive one. My hope is that even those authors and reviewers who think that the outcome on a manuscript should have been different walk away feeling that the experience was beneficial and that Cell Chemical Biology is a journal worth supporting.

Every month the editors of Cell Chemical Biology bring you highlights of the most recent chemical biology literature that impressed them with creativity and potential for follow up work. Our August 2016 selection includes a description of hydrogels with self-tunable stiffness that are used to profile lipid metabolites during stems cell differentiation, a look at whether we can find a drug repurposing solution to Zika virus infection, and an engineered RNA recognition motif (RRM).

For those who are working at the interface of chemistry and biology, chemical biology may seem like old news. Although most would agree that chemical biology is not yet a mature discipline like cell biology or physical chemistry, those who have dedicated their research careers to untangling the secrets of biological function using chemical approaches likely feel that chemical biology is a road well traveled. However, chemical biology is still in many ways a new kid on the block, and we, as editors of one of the leading journals dedicated to supporting the field, feel that it is our responsibility to help chemical biologists tell and hear each other’s stories as well as to help them place chemical biology contributions in the broader context.One way in which those thoughts are summarized, explained, and shared is through the review content that we publish. A useful review article is significantly more than a laundry list of facts: it is a snapshot of the thinking in the field delivered in a way that is both instructive for novices and deeply intellectually engaging for experts.Building on the description of a useful review article, an exceptional review article is one that not only informs and educates, but also provokes alternative ways of looking at a problem and inspires further research and discussion. A great review helps us not only to navigate the existing scientific literature and information overload, but leads us to discover new galaxies of scientific knowledge. We like to think that all of the review articles we publish are useful, and we hope that most of them are exceptional and play substantial roles in setting the research agenda for different fields we cover.Review articles are also a way in which editors engage more actively with the direction of the field. Most review articles published by Cell Chemical Biology are editorially commissioned, which means that the Editors decide on the topic for a review article and invite experts in the field to write it. Overall, there are many different ways in which editors identify a timely topic. Our ideas may crystallize while we browse through the existing literature, flip through meeting programs, watch webinars, or listen to talks at scientific conferences. We may get inspired by a newspaper article discussing a specific medical need, news of a drug approval, or a chance remark on social media. Often times, ideas pour in as we engage in conversations with members of the community or as we work with our authors and reviewers on shepherding the research papers submitted to Cell Chemical Biology through the peer review process. We also receive tips and suggestions from our Editorial Board members, who are our ambassadors and our eyes and ears in the community. Finally, some proposals are unsolicited and come to us through our presubmission inquiry process. These presubmission inquiries usually contain a brief explanation of why a certain topic would benefit from a synthesis and include a rough outline of the key points that the proposed review will cover, as well as a list of the key references that will be discussed.Regardless of where ideas and suggestions for our review articles come from, they all go through a process of careful evaluation before they become a formal invitation. Based on our experience, the best Cell Chemical Biology review articles are those that cover a topic of core current interest to chemical biologists, a topic that is undergoing rapid growth in terms of research interests, a scientific problem that requires major rethinking, a controversial issue with broad impact on the entire field, or a combination of all of these factors. Determining whether a topic we have in mind or a topic someone has proposed to us checks any of these broad guidelines is not trivial. It requires taking several steps back to look at the entire general area of research in which the given topic sits as well as related areas that may potentially be influenced by the discussion we publish. We consider both the quality and quantity of the research output that the potential review may cover because we want to publish reviews on topics that people actively care about. We also try to anticipate specific questions and issues that will be important points of debate and discussion in the near future, because great reviews don’t just appear—they are written by people who are passionate about carefully crafting their arguments and discussions and dedicated to delivering new galaxies of knowledge. This means that, on average, it takes about 8–12 months for a review article to go from idea to publication. Finally, we also take care to cover a variety of topics and issues that are of particular interest to chemical biologists and to invest effort into ensuring diversity in our review content. Unfortunately, this also means that we have to decline some of the unsolicited proposals to avoid overlap with what we already have in our review article pipeline.In the past, everyone on our editorial team has shared the responsibility for our review content. Although we enjoyed doing so, we felt that the journal, and the field, would benefit from a more focused and dedicated approach. Therefore, we have decided to expand our editorial team and bring on board a Reviews Editor who will lead our reviews strategy. We are pleased to announce that Michelle Arkin, Associate Professor of Pharmaceutical Chemistry and the Director of Biology at the Small Molecule Discovery Center at UCSF will serve as the Cell Chemical Biology Reviews Editor. Michelle’s research is focused on structure/function and chemical biology of allosterically regulated enzymes and protein-protein interactions (PPI). In addition, her lab has a strong interest in developing probes and drug leads to address mechanisms of neurodegeneration, cancer, and parasitic disease. Over the years, Michelle has co-authored several key review articles in the area of targeting PPI (see http://www.nature.com/nrd/journal/v3/n4/full/nrd1343.html and http://www.cell.com/cell-chemical-biology/fulltext/S1074-5521(14)00291-9) that stand as examples of the power of reviews to shape the direction of the field. We look forward to seeing what mark Michelle makes in her new role as our Reviews Editor.If you have an idea for a review, please email your suggestions to chembiol@cell.com.

It is March, and the spring is definitely in the air here in Cambridge, MA, USA where Cell Press offices are located. If we said that, like the nature around us itself, Cell Chemical Biology editorial team is ready to spring into action that would be an understatement. Ever since the first issue of Cell Chemical Biology came out two months ago, we have been working hard to spread our message across the field of chemical biology and broader biomedical community to raise visibility and awareness of all the meaningful changes we are enacting. In return, we have been getting messages of support from the community and we are grateful and humbled by your enthusiasm and encouragement. That type of overwhelmingly positive feedback strengthens our confidence that re-launching Chemistry & Biology under the name of Cell Chemical Biology was the right thing to do for the journal and the field.One of the key groups of people that we have been interacting with a great deal throughout this process is our Editorial Board. We reached out to some members of the Editorial Board more than two years ago to get initial reactions on the idea to change the title to Cell Chemical Biology and these conversations really helped us shape the vision for the future. Additionally, people on our Editorial Board continued to provide us with the advice on more specific questions, such as suggestions for potential review article content and hot topics that would benefit from critical discussion. We plan to follow up on many of those and use interesting review type content to bring out a more complex flavor of the journal.Lastly, our Editorial Board Members actively participated in the process of Editorial Board expansion that we just went through. In preparation for relaunch we approached our existing Editorial Board to share that one of the big components of our strategy for making Cell Chemical Biology a success will be centered around rethinking our scope and the types of studies that we want to publish. In addition to “traditional” chemical biology studies that use chemical tools to perturb, visualize and measure properties of biological systems to build a better view of molecular mechanism and physiology, or those that are centered on biochemical mechanism and how to engineer it to increase chemical diversity of biosynthetic small molecules, we want Cell Chemical Biology to be home for studies that ask questions about metabolism and metabolites, as well as small molecule-protein and small molecule-nucleic acid conjugates especially those that push our appreciation for what specific post-translational and epigenetic modifications are doing. We are also excited about studies that combine the use proteomics, lipidomics, metabolomics, glycomics and other methods that offer systems level view of biology and transform those insights into a deeper mechanistic understanding. Even this expanded list it not all, as we see exciting work being done across the range of traditional biological disciplines, such as genetics, cell biology, developmental biology, neurobiology, immunology, as well as more recent areas of stem cell research and synthetic biology. We believe that chemical biology touches all aspects of biological research and we wanted to highlight this through opening up our scope.We also want our Editorial Board to reflect the diversity of science that the journal is interested in, and together with the Chemistry & Biology Editorial Board Members we worked hard to identify the type of expertise that we need in order to cover all the subject matter we were getting excited about, and find the diverse group of people to bring on board. Over the last several months we welcomed many new Editorial Board Members that have diverse scientific interests, and hail from all over the world. Additionally they also come from different stages in their scientific careers and we brought on board not only well-established senior scientists, but an exceptional group of up-and-coming next generation leaders.We are excited to have this fantastic group of advisors and ambassadors supporting Cell Chemical Biology. You may wonder what it is that our Editorial Board Members do, and it is a fair question. Our Editorial Board members don’t handle manuscripts and are not responsible for overseeing the peer review process or serving as the default reviewer pool. What we expect from our Editorial Board members is to be our ambassadors in their local and global scientific communities, and we count on them to promote the journal as a place for their colleagues and their field to publish exciting results. We depend on our Editorial Board Members to tell us what’s exciting in their area of research and what the future might bring, as well as to alert us if there are any changes to current best practices and standards in the field that we should know about. This helps us evolve our policies and criteria. Additionally, we rely on our Editorial Board Members to help us untangle complicated editorial decisions or adjudicate disputes that sometimes erupt between authors and reviewers.Editorial Board Members are our go-to group of scientists when we are thinking about new article formats, new features, or new initiatives and we look to them to point out not only exciting aspect of changes that we are thinking about but openly voice their concerns as well. For example, one significant concern that some members of our Editorial Board had during the relaunch process was that our emphasis on tackling difficult biological problems, problems that those in biology care deeply about will negatively impact the quality of chemistry we publish and rob us of our chemical heritage. We are still talking about this and have yet to reach the point where we feel this issue is put to rest, but as with other issues in the past these types of discussions help us understand the thinking and concerns in the field, and we are thrilled to have the Editorial Board that continues to challenge us to do right by the field.From day one, our goals for the journal have been lofty – we want Cell Chemical Biology to be home for the most exciting chemical biology research where chemical creativity meets biological complexity, and the two enhance each other to create insights into toughest scientific questions. We feel that having enthusiastic group of advisors and ambassadors on our Editorial Board will make achieving these goals easier and definitely more enjoyable.

Chemical biology is one of those fields that needs a bit of explaining. It is definitely a subfield within chemistry and at the same time it is now clear that it is an emerging discipline in both biology and translational research. It straddles the chemistry-biology-medicine continuum more effectively and better than any other named research endeavor (http://www.sciencedirect.com/science/article/pii/S1074552114002543).Having said that, I recognize that some will not be as convinced as I am, and as the editor of one of the most visible chemical biology journals, I spend a good amount of time thinking about what Cell Chemical Biology can do to change the perceptions and solidify the role of chemical biology as a major bridge between chemical, biological, and medical sciences. This is, of course, a very tall order, but I know that the journal, its editors, our editorial board members, authors, reviewers, and readers are bold and adventurous and sense that the community is heading in this direction.Some steps we take are huge, like making a decision to re-launch the journal as Cell Chemical Biology and better position ourselves as a basic biology journal while not relinquishing our role as a basic chemistry journal (http://www.cell.com/cell-chemical-biology/fulltext/S2451-9456(16)00002-7). Or shifting our scope and interests towards many of the fields in which the impact of chemical thinking and a chemical way of doing things is starting to be the norm, helping the fields progress at an accelerated rate. Some of those fields include cancer research, metabolism and physiology, microbiome and microbiology, systems and synthetic biology, and drug discovery and development, and they are all represented in Cell Chemical Biology: Best of 2016, a free to access and free to download collection of the most read papers we published last year (http://info.cell.com/best-of-cell-chemical-biology-2016).I encourage you to take a look at this collection as it provides a nice overview of the diversity of research ideas and approaches that reflect the breadth of chemical biology. The field itself, however, is far more innovative and productive than one journal can ever hope to cover, so in order to promote and showcase some of the chemical biology stories that have been published in other journals, we decided to launch the Cell Chemical Biology Call.We borrowed the name and the format from Cell Systems, one of our sister journals,. For them, the Call was an invitation to their community to help the journal define the basic principles of an exceptionally multidisciplinary and quickly evolving field such as systems biology and to discuss newly published papers that encapsulate those principles (http://www.cell.com/cell-systems/fulltext/S2405-4712(15)00193-3). Additionally, the Cell Systems Call offered a view into the future and where each of the ideas is heading.What struck me while considering the basic idea behind this format and reading some of the Cell Systems Calls, which are all published under the title “Principles of Systems Biology,” is how engaging these highlights are and how much interesting yet easy-to-digest information they offer. I also started noticing parallels between the two fields and some conceptual commonalities. Both systems biology and chemical biology are exceptionally broad and interface with a number of different, more established fields. They are also relative newcomers, and researchers in both fields have invested major efforts to carve out their scientific identities. This also means that both fields are vibrant and growing, with many early career researchers entering the arena using tools and strategies based on chemical or systems level thinking and asking the types of biological questions that can only be addressed using these new tools. Finally, and fundamentally, because both fields are multidisciplinary, they are perhaps more difficult and require more effort to define and explain.The Cell Chemical Biology Call will offer engaging glimpses of the vast array of chemical biology literature as well as providing insight into modern chemical biology thought and the future of the chemical biology field. Each Call is a brief 200 word summary that highlights the basic principles behind a recently published paper and an answer to the question “what next?” Unlike the Cell Systems Call, where anyone may submit their article, all the contributions to the Cell Chemical Biology Call are invited by the editors and they signal the types of questions we view as timely and relevant. We will also not shy away from highlighting stories that may seem tangential to chemical biology research interests if we feel that future directions would benefit from more chemical biology involvement.Three recent studies highlighted in the first ever Cell Chemical Biology Call fit these rough guidelines well, as they highlight a cell biology story in which the researchers find link between mitochondria and proteostasis, thus opening the need for new chemical tools to dissect this relationship further; a protein engineering story in which researchers develop a new class of enzyme-based “plug-and-play” biosensors; and a clinically relevant gut microbiome story in which researchers take a closer look at the fungal members of our microbiome and their metabolic and chemical diversity.I hope you take a look at “Principles of Chemical Biology: From MAGIC to Gut Fungi, via ”Plug-And-Play” Biosensors” (http://www.cell.com/cell-chemical-biology/fulltext/ S2451-9456(17)30101-0) and enjoy the inaugural Cell Chemical Biology Call. I also hope you take these highlights to be a call to action, a call to ask different and more provocative scientific questions, and a call to talk more frequently and perhaps even more passionately about what chemical biology is and what it can do to bridge the venerable fields of chemistry, biology and medicine.

Every month I have the privilege of selecting a handful of chemical biology papers that were published elsewhere but that caught my imagination as something worthy of further remarks. Making a selection out of hundreds if not thousands of chemical biology papers published across biology and chemistry journals is not an easy task, and it is not something that I take lightly. I evaluate the science the papers report to determine whether they offer an exciting nugget of new chemical biology insight, and I also examine closely whether the papers I highlight represent an exceptional illustration of the power of interdisciplinary efforts positioned at the interface of chemistry and biology to advance our basic understanding of biology.What I look for is the true synergy in which the one type of study, let’s call it biology, would not have been possible without the other type of study, meaning chemistry. Alternatively, I look to identify scientific puzzles in which the next step in the big picture story would benefit greatly from some chemical thinking or chemical tools in the hope that I can inspire someone in the community to step up to the challenge. This editorial, however, is not about the selection process—I wrote about that some time ago (http://crosstalk.cell.com/blog/making-selections-for-cell-chemical-biology-select)—but rather about an end-of-the-year look at the papers I covered in 2016 and seeing where are they now. Over the last year, I featured 27 papers published across 15 different journals. As it happens, and not surprisingly, Nature Chemical Biology has published a significant proportion of the chemical biology stories that I thought were worth further discussion. I also discovered interesting chemical biology stories in Cell, Cancer Cell, Nature, Nature Methods, Cell Metabolism, Nature Communications, ACS Central Science, PNAS, and many other places. To me, this speaks volumes about how widely spread the research interests of chemical biologists are and how accepted their way of interdisciplinary thinking seems to be.Diving deeper into the main themes this year, at least based on the work I chose to single out each month, it seems that infectious diseases and cancer were in the forefront of many people’s minds, including mine. Earlier this year, there was no escaping news on the Zika virus, and the scientific community has responded to this global health crisis swiftly and with great earnestness to develop a better understanding of the virus; its interaction with the host, especially during embryonic development; and the vaccines or drugs for treatment. At Cell Press, we supported these efforts by making the papers related to the Zika virus free to publish and access via our public health portal dedicated to Zika virus research (http://www.cell.com/public-health-zika-virus). The study in this area that caught my eye is on this portal and freely available, as it was published earlier this year in Cell Host & Microbe and focused on drug repurposing efforts to accelerate Zika drug discovery (http://www.cell.com/cell-chemical-biology/fulltext/S2451-9456(16)30250-1).When it comes to cancer research, 2016 was also a year of major news in many ways due to the launch of the Cancer Moonshot, the effort of the United States government to accelerate cancer research. One of the most intriguing papers I read this year falls broadly into the cancer biology area. The work in question was published in Cell Systems and looked into whether a small molecule inhibitor or a genetic knockout is better when it comes to silencing a protein involved in a signaling network (http://www.cell.com/cell-chemical-biology/fulltext/S2451-9456(16)30056-3). The intersection with the cancer field here comes from the fact that the focus of the work was on the Raf–MEK–ERK cascade, which is notorious for its role in cancer, and the insights point toward a situation in which small molecule inhibitors are more efficient, but only if the players in the signaling cascade are linked via a negative feedback loop.However, when it comes to absolute winners this year in terms of their prominence on our Select pages, this honor goes to the endogenous small molecules that govern our physiology, and among them cholesterol reigns supreme. This year we learned that cholesterol metabolism is the Achilles’ heel of glioblastoma (http://www.cell.com/cell-chemical-biology/fulltext/S2451-9456(16)30398-1), that cholesterol regulates developmental biology via the Hedgehog (Hh) cell-cell signaling pathway (http://www.cell.com/cell-chemical-biology/fulltext/S2451-9456(16)30304-X), and that none other than cholesterol is an endogenous ligand for the estrogen-related receptor α (ERRα) (http://www.cell.com/cell-chemical-biology/fulltext/S2451-9456(16)30018-6). What fascinates me about all these endogenous small molecules in which our cells are is how much we are yet to discover about their chemical diversity and biological functions. In this area, chemical biology is exceptionally well poised to take the lead in deciphering all the details, and I would like to see more of these stories in the future on the pages of Cell Chemical Biology as well as in biological and chemical journals everywhere.Going back to “where are they now” question, I took a closer look at the amount of online attention each of the papers I selected received. Based on the Altmeric score, the paper that got the most coverage on social media, blogs, and news outlets is an incredible report on the initial results of developing opioid painkillers that have minimal side effects and are unlikely to lead to addiction (http://www.cell.com/cell-chemical-biology/fulltext/S2451-9456(16)30304-X). For those with chronic pain issues, this work offers new hope, although the study is just a first step toward a new generation of painkillers.Overall, if you are a chemical biologist, you have likely found a great deal of interesting research findings and reviews to enjoy this year. I hope you have also found some of my highlights to be of interest as well. As of the writing of this editorial, the future of the Cell Chemical Biology Select is somewhat up in the air: we are yet to make a decision on whether this is the most effective way to highlight the most interesting developments in the field. We are exploring alternative options, and if you have suggestions, we are glad to take them on board. For now, I leave you with season greetings and happy holiday wishes. Here’s hoping for a stellar and productive 2017!

From its inception in 1994, Chemistry & Biology has had a strong interest in publishing articles and reviews describing and discussing research related to natural product biosynthesis. The second issue highlighted the exciting elucidation of the vitamin B12 biosynthetic pathway [Scott, A.I. (1994). Chem. Biol. 1, xxiv–xxv], thus signaling the journal's interest in the field. The interest has not faded over the years, although the types of questions and approaches taken have diversified and grown in different directions, as manifested by the content of the current issue, which includes several articles that can be broadly classified in the natural product biosynthesis category.

The number and quality of known membrane protein structures has been steadily increasing over the last decade. By commissioning reviews for the Special Review Collection under the title “Structure Meets the Membrane,” the Editors aim to highlight a number of major advances in the determination of membrane protein structures.The Special Review Collection includes eleven contributions to be published in the next three issues (October through December): a review of glutamate receptor ion channels by Mark Mayer, a discussion of the role of electron crystallography in structural biology of membrane proteins by Tamir Gonen and colleagues, an overview of mechanosensitive channels by Douglas Rees and colleagues, a survey of computational methods to study membrane proteins by Mark S.P. Sansom and colleagues, a perspective on the role of lipids by Kai Simons and colleague, new insights into Na+,K+-ATPase by Chikashi Toypshima and colleagues, a discussion of structural genomics approaches to membrane protein structure by Wayne Hendrickson, a review of bacterial pentameric ligand-gated ion channels by Pierre-Jean Corringer and colleagues, a discussion of membrane protein dynamics gleaned through the use of EPR spectroscopy by Hassane Mchaourab, an exploration of issues surrounding design of membrane proteins presented by Jeffrey G. Saven, and an overview of proteins and protein domains that interact with a membrane by Mark Lemmon and colleagues.We thank the authors as well the reviewers who were involved in the process of shaping these contributions. We believe that the biological community will increasingly benefit from the ever-growing body of structural information on membrane proteins, and we hope that the discussions included in the Special Review Collection will contribute to this laudable goal.

Although the structure of the molecular chaperone Hsp90 has been extensively characterized by X-ray crystallography, the nature of the interactions between Hsp90 and its client proteins remains unclear. We present results from a series of spectroscopic studies that strongly suggest that these interactions are highly dynamic in solution. Extensive NMR assignments have been made for human Hsp90 through the use of specific isotopic labeling of one- and two-domain constructs. Sites of interaction of a client protein, the p53 DNA-binding domain, were then probed both by chemical shift mapping and by saturation transfer NMR spectroscopy. Specific spectroscopic changes were small and difficult to observe, but were reproducibly measured for residues over a wide area of the Hsp90 surface in the N-terminal, middle and C-terminal domains. A somewhat greater specificity, for the area close to the interface between the N-terminal and middle domains of Hsp90, was identified in saturation transfer experiments. These results are consistent with a highly dynamic and nonspecific interaction between Hsp90 and p53 DNA-binding domain in this chaperone-client system, which results in changes in the client protein structure that are detectable by spectroscopic and other methods.

The Editors of Chemistry & Biology would like to thank all of the authors who contributed to the special anniversary issue as well as all of the reviewers who provided us and the authors with valuable comments.

We use NMR spectra to determine protein–protein contact sites by observing differences in amide proton hydrogen–deuterium exchange in the complex compared to the free protein in solution. Aprotic organic solvents are used to preserve H/D labeling patterns that would be scrambled in water solutions. The binding site between the mammalian co-chaperone Aha1 with the middle domain of the chaperone Hsp90 obtained by our H/D exchange method corresponds well with that in the X-ray crystal structure of the homologous complex from yeast, even to the observation of a secondary binding site. This method can potentially provide data for complexes with unknown structure and for large or dynamic complexes inaccessible via NMR and X-ray methods.

We recently asked our Editorial Board members to answer the following question: “what paper would you like to read in the January 2026 issue of Cell Chemical Biology?” We received more than forty responses, and if you are interested in what our Editorial Board members came up with, you can read all of the titles in the editorial that accompanied our January 2016 issue (http://www.cell.com/ccbio/fulltext/S2451-9456(16)00002-7). The world cloud you see here will also hopefully help to orient you with respect to some of the big themes that were on the minds of those who answered our question.

In September 1994, the first issue of a new journal called Chemistry & Biology was published. The founding editors, Stuart Schreiber and K.C. Nicolaou, opened the issue with an editorial titled “Crossing the Boundaries,” emphasizing the impact of merging the two title disciplines. They envisioned the new journal to be a potent and vocal facilitator of the process of blurring and leaping boundaries, to arm biologists with unique chemical tools for delving deeper into the investigation of life, and to provide chemists with a view of biological frontiers.

Twenty years after the publication of the first draft of the human genome, our knowledge of the human proteome is still fragmented. The challenge of translating the wealth of new knowledge from genomics into new medicines is that proteins, and not genes, are the primary executers of biological function. Therefore, much of how biology works in health and disease must be understood through the lens of protein function. Accordingly, a subset of human proteins has been at the heart of research interests of scientists over the centuries, and we have accumulated varying degrees of knowledge about approximately 65% of the human proteome. Nevertheless, a large proportion of proteins in the human proteome (∼35%) remains uncharacterized, and less than 5% of the human proteome has been successfully targeted for drug discovery. This highlights the profound disconnect between our abilities to obtain genetic information and subsequent development of effective medicines. Target 2035 is an international federation of biomedical scientists from the public and private sectors, which aims to address this gap by developing and applying new technologies to create by year 2035 chemogenomic libraries, chemical probes, and/or biological probes for the entire human proteome.

This issue marks 20 years since the first issue of Structure was published, becoming the first journal exclusively devoted to structural biology. The cover of the first issues in 1993 prominently featured the journal’s motto: “Form and function in modern biology” (Figure 1Figure 1). This motto, now printed on the journal’s masthead, continues to capture the emphasis Structure places on publishing studies that provide critical structural insights into biological function, mechanism, and evolution. The journal was launched in a visionary effort by Wayne A. Hendrickson and Carl-Ivar Branden, who served as its editors and later joined by Alan Fersht. This editorial team led the journal for a number of years and through several major changes. In 1998, another journal, Folding and Design, was integrated into Structure, and for the next couple of years the journal was entitled Structure with Folding and Design. In the early 2000s, Structure with Folding and Design became part of Cell Press as Structure, reinstating the original name of the journal. In 2003, Andrej Sali, Christopher D. Lima, and Jody Puglisi were recruited as scientific editors for Structure, reinforcing Cell Press’ strong position that editorial decisions for the journal should be influenced by academic scientists whose areas of expertise span a broad swath of structural biology. Lima and Sali remain with the journal 10 years later.Figure 1Cover of the Prelaunch Introductory Issue of StructureThe cover highlights the ongoing focus of the journal on providing a home to articles describing exciting structural insights that further understanding of modern biology. Currently, the journal has evolved to include analysis of high relevance for basic science, as well as biotechnology and translational sciences.View Large Image | View Hi-Res Image | Download PowerPoint SlideThis Special Anniversary Issue was commissioned to celebrate the 20 year milestone by featuring commentaries, perspectives, and reviews on a variety of topics that reflect the growing diversity within the field. In their commentary, Seth Cooper, Firas Khatib, and David Baker introduce the idea of citizen science and outline why structural biology might benefit from embracing crowdsourcing approaches (Cooper et al., 1482). Helen Berman et al. (pp. 1485) provide historical perspective on the Protein Data Bank (PDB) and how the community transformed it into its current role as a central resource and advocate for structural biology. Maya Topf and colleagues highlight recent advances in computational methods that improve the ability to interpret and integrate different structural biology techniques, leading to improved analysis of macromolecular assemblies (Thalassinos et al., 1500). Julie Forman-Kay and Tanja Mittag (pp. 1492) offer their perspective on intrinsically disordered proteins and their important contributions to complex biological functions. Allosteric conformational barcodes is the idea put forward by Ruth Nussinov and colleagues in a review that formalizes thinking about populations of protein conformational states and their functional roles (Nussinov et al., 1509). In their review, Julien Marcoux and Carol Robinson (pp. 1541) reflect on the two decades of structural biology in gas phase and use some recent examples to highlight the strengths of mass spectrometry (MS) as a tool of structural biology. Recent developments in cryoelectron tomography (cryo-ET) take center stage in the review by Jan Harapin, Matthias Eibauer and Ohad Medalia that highlights current opportunities and limitations of applying cryo-ET to vitrified cells and tissues (Harapin et al., pp. 1522). Torsten Schwede (pp. 1531) provides a review of methods for predicting 3D molecular structure and discusses how computational modeling is shifting from smaller systems to macromolecular assemblies. Finally, Wolfgang Baumeister, Friedrich Forster, and colleagues review exciting breakthroughs in structural studies of the 26S proteasome, a large macromolecular complex, by focusing on integrative approaches to tackle analysis of this system (Forster et al., pp. 1551).Structure has made several changes over the last year with the aim to better serve the community. Last summer, we introduced Short Articles that focus on exciting structural observations that make a discrete point of strong general significance. We transitioned to a continuous publication model and now publish all accepted articles online ahead of print, which significantly decreased the time between acceptance and publication to 5 weeks on the average. We joined Twitter (@Structure_CP) to share information and to build a strong structural biology community in this type of social media. This summer witnessed publication of the first “The Best of Structure” collection, which features a selection of 2012 articles that elicited the highest attention of our readers. Access to this digital collection is free and we encourage everyone to take a look (http://onlinedigeditions.com/publication/frame.php?i=167133&p=&pn=&ver=flex). Finally, looking to the future, we plan to retire Ways & Means and Technical Advances in January 2014 and replace them with a new article format, Resources, that will mirror similar formats in the other Cell Press journals. The Resource articles will highlight significant technical advances and/or major databases that are of value and interest to the broad structural biology community.The journal and its editors remain focused on publishing exciting structural biology reports, irrespective of the method used. As structural biology has evolved over the past two decades, Structure, too, has evolved with the field and is now home for a variety of reports that illuminate biology through application of X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy, electron microscopy (EM), MS, small angle scattering, computational biology, single molecule studies, and integrative structural biology, to name just a few approaches. We expect the commitment to all facets of structural biology to remain a cornerstone of the journal for years to come. We look forward to the future, fulfilling our mission to support structural biology as it continues to provide critical contributions to basic science, biotechnology, and translational sciences.

As you browse through this issue of Chemistry & Biology, or if you visit our website at http://www.chembiol.com in search of contact information, you might notice some changes to the lists of our Editors and Editorial Board members. We are delighted to announce that Dr. Craig M. Crews has joined our team of Editors. Dr. Crews is a Professor of Molecular, Cellular, and Developmental Biology, Professor of Chemistry and Professor of Pharmacology at Yale University, New Haven, Connecticut, USA, and his research interests include natural product synthesis, mechanism of action studies, and the use of small molecules to control cellular functions, such as protein degradation and proliferation. On the other hand, we are sorry to lose the services of Dr. Ronald R. Breaker, who started his tenure as the Editor of Chemistry & Biology in 2002. We would like to express our gratitude to Dr. Breaker, who has made significant contributions to Chemistry & Biology and the research community we serve, in his role as an Editor. Finally, it gives us great pleasure to welcome Dr. Breaker to the journal's Editorial Board, thus continuing his involvement with the journal and communicating exciting scientific reports from research done at the chemistry/biology interface.

Spring might not be yet in the air here in the Northeastern part of United States, where the Chemistry & Biology editorial offices are located, but change to the editorial team has arrived. We are excited to introduce the newest Editor of Chemistry & Biology, Dr. Hiroaki Suga, who joined the journal a few weeks ago. Dr. Suga is a professor at the University of Tokyo, School of Science, in Tokyo, Japan, and his key research interests transcend the limits of two disciplines, chemistry and biology, to create an amalgamation of projects and ideas rooted in both fields. His current research interests range from genetic code reprogramming and the development of new biological peptides to understanding and targeting bacterial quorum sensing. We are positive that his expertise and broad scientific interests will be a valuable asset to both the journal and the chemical biology community that we support.At this time, we would also like to announce that Dr. Michael Famulok will be stepping down as an editor of the journal after serving in this role since 2001. During his tenure with the journal, Dr. Famulok has made outstanding contributions to the journal, advocating high editorial standards, publishing cutting-edge science, and engaging the community. Dr. Famulok will continue to work closely with the journal as a new editorial board member.The editorial team remains committed to growing and improving our content, and we hope that you will see the journal as we do, as a collaboration between authors, reviewers, editors, and readers, or to paraphrase an African proverb, “it takes an energetic and creative scientific community to make a leading journal.”