Biochemistry

Unanticipated mechanisms of covalent inhibitor and synthetic ligand cobinding to PPARγ

1. Jinsai Shang
2. Douglas J Kojetin

• Curated by eLife

  eLife Assessment

  This landmark study elucidates the intricate structural mechanisms by which both covalent and non-covalent synthetic ligands can co-occupy the binding pocket of the nuclear receptor transcription factor PPARγ. Through a compelling integration of structural, biochemical, and biophysical evidence, the authors challenge the reliability of two commonly used covalent inhibitors. These findings have far-reaching implications for the broader field of nuclear receptor research. This work will be of high interest to structural biologists and biochemists exploring ligand interactions within the nuclear receptor superfamily.

Reviewed by eLife

Crystal structure and catalytic mechanism of PL35 family glycosaminoglycan lyases with an ultrabroad substrate spectrum

1. Lin Wei
2. Hai-Yan Cao
3. Ruyi Zou
4. Min Du
5. Qingdong Zhang
6. Danrong Lu
7. Xiangyu Xu
8. Yingying Xu
9. Wenshuang Wang
10. Xiu-Lan Chen
11. Yu-Zhong Zhang
12. Fuchuan Li

• Curated by eLife

  eLife Assessment

  This manuscript reports on the crystal structures of two glycosaminoglycan (GAG) lyases from the PL35 family, along with in vitro enzyme activity assays and comprehensive structure-guided mutagenesis. While the study provides structural insights into the broad substrate specificity of these enzymes, the incomplete structural models, lack of key data such as Mn²⁺ binding confirmation, and reliance on basic docking methods diminish the overall impact. Although the work is useful for specialists in carbohydrate-active enzymes, additional data, and more rigorous analysis are required to present a complete study.

Reviewed by eLife

Structural insights into human propionyl-CoA carboxylase (PCC) and 3-methylcrotonyl-CoA carboxylase (MCC)

1. Fayang Zhou
2. Yuanyuan Zhang
3. Yuyao Zhu
4. Qiang Zhou
5. Yigong Shi
6. Qi Hu

• Curated by eLife

  eLife Assessment

  This study presents the cryo-EM structures of two human biotin-dependent mitochondria carboxylases involved in various biological pathways, including the metabolism of certain amino acids, cholesterol, and odd chain fatty acids. The cryo-EM structures offer a valuable addition to the structural description of biotin-dependent carboxylases and provide solid evidence to support the major conclusions of this study. This paper would be of interest to biochemists and structural biologists working on biotin-dependent carboxylases.

Reviewed by eLife

Transcriptome-wide identification of 5-methylcytosine by deaminase and reader protein-assisted sequencing

1. Jiale Zhou
2. Ding Zhao
3. Jinze Li
4. Deqiang Kong
5. Xiangrui Li
6. Renquan Zhang
7. Yuru Liang
8. Xun Gao
9. Yuqiang Qian
10. Di Wang
11. Jiahui Chen
12. Liangxue Lai
13. Yang Han
14. Zhanjun Li

• Curated by eLife

  eLife Assessment

  This potentially useful study introduces an orthogonal approach for detecting RNA modification, without chemical modification of RNA, which often results in RNA degradation and therefore loss of RNA molecules. While the authors have improved the work compared to a previous version, uncertainty regarding false positive and false negative rates leave the evidence for the broad applicability of the method incomplete. If properly validated, the approach might be of particular interest for sites where modifications are rare.

Reviewed by eLife

Large-scale characterization of drug mechanism of action using proteome-wide thermal shift assays

1. Jonathan G Van Vranken
2. Jiaming Li
3. Julian Mintseris
4. Ting-Yu Wei
5. Catherine M Sniezek
6. Meagan Gadzuk-Shea
7. Steven P Gygi
8. Devin K Schweppe

• Curated by eLife

  eLife Assessment

  The study provides a valuable showcase of a workflow to perform large-scale characterization of drug mechanisms of action using proteomics in which on-target and off-targets of 166 compounds using proteome solubility analysis in living cells and cell lysates were determined. The evidence supporting the claims of the authors is solid, however, the inclusion of more replicate experiments and more statistical rigor would have strengthened the study. This will be of broad interest to medicinal chemists, toxicologists, computational biologists and biochemists.

Reviewed by eLife

A new class of receptors: Lipids regulate mammalian Gsα-stimulated adenylyl cyclase activities via their membrane anchors

1. Marius Landau
2. Sherif Elsabbagh
3. Harald Gross
4. Adrian Fuchs
5. Anita C.F. Schultz
6. Joachim E. Schultz

• Curated by eLife

  eLife Assessment

  This manuscript describes a valuable study of a new lipid-mediated regulation mechanism of adenylyl cyclases. The biochemical evidence provided is convincing, but more evidence for regulation by lipids under natural cellular processes would be interesting. This manuscript will be of interest to all scientists working on lipid regulation and adenylyl cyclases.

Reviewed by eLife, Arcadia Science

The intrinsically disordered N-terminus of SUMO1 is an intramolecular inhibitor of SUMO1 interactions

1. Sebastian M Richter
2. Fan Jin
3. Tobias Ritterhoff
4. Aleksandra Fergin
5. Eric Maurer
6. Andrea Frank
7. Michael Daube
8. Alex Hajnal
9. Rachel Klevit
10. Frauke Gräter
11. Annette Flotho
12. Frauke Melchior

• Curated by eLife

  eLife assessment

  This work demonstrates an important regulatory role of the N-terminal disordered tail of small ubiquitin-like modifier (SUMO) proteins, which modulate the function of various proteins in eukaryotic cells. The authors present convincing evidence that the N-terminal tail of SUMO inhibits SUMO's interaction with downstream effector proteins and SUMOylation targets, and that this regulatory mechanism depends on the SUMO paralogue or the phosphorylation of the N-terminal tail. This discovery significantly advances the field by providing a possible explanation of how SUMO paralogues select their effectors and SUMOylation targets.

Reviewed by eLife

Elucidating the kinetic and thermodynamic insight into regulation of glycolysis by lactate dehydrogenase and its impact on tricarboxylic acid cycle and oxidative phosphorylation in cancer cells

1. Siying Zeng
2. Yuqi Wang
3. Minfeng Ying
4. Chengmeng Jin
5. Chang Ying
6. Di Wang
7. Hao Wu
8. Xun Hu

• Curated by eLife

  eLife assessment

  This study presents an assessment of the effect of lactate dehydrogenase (LDH) inhibition on the activity of glycolysis and tricarboxylic acid cycle. The data were collected and analyzed using solid and validated methodology. This paper makes a useful contribution to the field as it considers a control analysis of LDH flux.

Reviewed by eLife

Bioorthogonal labeling of chitin in pathogenic Candida species reveals biochemical mechanisms of hyphal growth and homeostasis

1. Caroline Williams
2. Bella R. Carnahan
3. Stephen N. Hyland
4. Catherine L. Grimes

Reviewed by PREreview

Elucidating ATP’s Role as Solubilizer of Biomolecular Aggregate

1. Susmita Sarkar
2. Saurabh Gupta
3. Chiranjit Mahato
4. Dibyendu Das
5. Jagannath Mondal

• Curated by eLife

  eLife assessment

  The authors combined molecular dynamics simulations and experiments to study the role of ATP as a hydrotrope of protein aggregates. The topic is of major current interest and thus the study potentially makes an important contribution to the community. With the revised version, the level of evidence is considered generally solid, although there remains concern regarding the unusually high ATP concentration used in the simulation.

Reviewed by eLife