Acrylamides are the most commonly used warheads of targeted covalent inhibitors (TCIs) directed at cysteines; however, the reaction mechanisms of acrylamides in proteins remain controversial, particularly for those involving protonated or unreactive cysteines. Using the combined semiempirical quantum mechanics (QM)/molecular mechanics (MM) free energy simulations, we investigated the reaction between afatinib, the first TCI drug for cancer treatment, and Cys797 in the EGFR kinase. Afatinib contains a -dimethylaminomethyl (-DMAM) substitution which has been shown to enhance the intrinsic reactivity and potency against EGFR for related inhibitors. Two hypothesized reaction mechanisms were tested. Our data suggest that Cys797 becomes deprotonated in the presence of afatinib and the reaction proceeds via a classical Michael addition mechanism, with Asp800 stabilizing the ion-pair reactant state -DMAM/C797 and the transition state of the nucleophilic attack. Our work elucidates an important structure-activity relationship of acrylamides in proteins.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11100610 | PMC |
| http://dx.doi.org/10.1101/2024.02.18.580887 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Integrated metabolomic and transcriptomic strategies to reveal adaptive mechanisms in barley plant during germination stage under waterlogging stress.
J Plant Res
January 2025
College of Marine and Biological Engineering, Yancheng Institute of Technology, Yancheng, 224002, Jiangsu, China.
Barley (Hordeum vulgare L.) is an important cereal crop used in animal feed, beer brewing, and food production. Waterlogging stress is one of the prominent abiotic stresses that has a significant impact on the yield and quality of barley.
View Article and Find Full Text PDFAn involvement of a new zinc finger protein PbrZFP719 into pear self-incompatibility reaction.
Plant Cell Rep
January 2025
State Key Laboratory of Crop Genetics and Germplasm Enhancement, Saya Institute of Nanjing Agricultural University, Nanjing Agricultural University, Nanjing, 211800, China.
This study indicated that the CCHC-type zinc finger protein PbrZFP719 involves into self-incompatibility by affecting the levels of reactive oxygen species and cellulose content at the tips of pollen tubes. S-RNase-based self-incompatibility (SI) facilitates cross-pollination and prevents self-pollination, which in turn increases the costs associated with artificial pollination in fruit crops. Self S-RNase exerts its inhibitory effects on pollen tube growth by altering cell structures and components, including reactive oxygen species (ROS) level and cellulose content.
View Article and Find Full Text PDFHuman response times are governed by dual anticipatory processes with distinct neural signatures.
Commun Biol
January 2025
Department of Neuroscience, University of Pennsylvania, Philadelphia, PA, USA.
Human behavior is strongly influenced by anticipation, but the underlying neural mechanisms are poorly understood. We obtained intracranial electrocephalography (iEEG) measurements in neurosurgical patients as they performed a simple sensory-motor task with variable (short or long) foreperiod delays that affected anticipation of the cue to respond. Participants showed two forms of anticipatory response biases, distinguished by more premature false alarms (FAs) or faster response times (RTs) on long-delay trials.
View Article and Find Full Text PDFCell-free DNA release following psychosocial and physical stress in women and men.
Transl Psychiatry
January 2025
Department of Genetic Psychology, Faculty of Psychology, Ruhr-University Bochum, Universitätsstraße 150, Bochum, Germany.
Cell-free DNA (cfDNA) is continuously shed by all cells in the body, but the regulation of this process and its physiological functions are still largely unknown. Previous research has demonstrated that both nuclear (cf-nDNA) and mitochondrial (cf-mtDNA) cfDNA levels increase in plasma in response to acute psychosocial and physical stress in males. This study further investigated these findings by testing 31 female participants (16 using oral hormonal contraception and 15 not using oral hormonal contraception), and the results were subsequently compared with those of 16 male participants.
View Article and Find Full Text PDFMultifaceted interplays between the essential players and lipid peroxidation in ferroptosis.
J Genet Genomics
January 2025
Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China; Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China. Electronic address:
Ferroptosis, a type of programmed cell death, represents a distinct paradigm in cell biology. It is characterized by the iron-dependent accumulation of reactive oxygen species, which induce lipid peroxidation (LPO), and is orchestrated by the interplay between iron, lipid peroxides, and glutathione. In this review, we emphasize the frequently overlooked role of iron in LPO beyond the classical iron-driven Fenton reaction in several crucial processes that regulate cellular iron homeostasis, including iron intake and export as well as ferritinophagy, and the emerging roles of endoplasmic reticulum-resident flavoprotein oxidoreductases, especially P450 oxidoreductases, in modulating LPO.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!