The KDM5/JARID1 family of Fe(II)- and α-ketoglutarate-dependent demethylases removes methyl groups from methylated lysine 4 of histone H3. Accumulating evidence supports a role for KDM5 family members as oncogenic drivers. We compare the in vitro inhibitory properties and binding affinity of ten diverse compounds with all four family members, and present the crystal structures of the KDM5A-linked Jumonji domain in complex with eight of these inhibitors in the presence of Mn(II). All eight inhibitors structurally examined occupy the binding site of α-ketoglutarate, but differ in their specific binding interactions, including the number of ligands involved in metal coordination. We also observed inhibitor-induced conformational changes in KDM5A, particularly those residues involved in the binding of α-ketoglutarate, the anticipated peptide substrate, and intramolecular interactions. We discuss how particular chemical moieties contribute to inhibitor potency and suggest strategies that might be utilized in the successful design of selective and potent epigenetic inhibitors.
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http://dx.doi.org/10.1016/j.chembiol.2016.06.006 | DOI Listing |
J Chem Inf Model
January 2025
Key Laboratory for Photonic and Electronic Bandgap Materials, Ministry of Education, College of Chemistry and Chemical Engineering, Harbin Normal University, Harbin 150025, China.
Tryptophan participates in important life activities and is involved in various metabolic processes. The indole and aromatic binuclear ring structure in tryptophan can engage in diverse interactions, including π-π, π-alkyl, hydrogen bonding, cation-π, and CH-π interactions with other side chains and protein targets. These interactions offer extensive opportunities for drug development.
View Article and Find Full Text PDFFront Antibiot
May 2024
Laboratory of Bacteriology, Rocky Mountain Laboratories, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, United States.
Recent reports from the Centers for Disease Control and Prevention approximate 500,000 cases of Lyme disease in the United States yearly, a significant economic burden on the healthcare system. The standard treatment for Lyme disease includes broad-spectrum antibiotics, which may be administered for extensive periods of time and result in significant impacts to the patient. Recently, we demonstrated that , the causative agent of Lyme disease, is uniquely dependent upon peptide acquisition via an oligopeptide transport (Opp) system.
View Article and Find Full Text PDFNarra J
December 2024
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Erciyes University, Kayseri, Turkey.
The therapeutic potential of bitter leaf ( Del.) has been established both empirically and in various scientific investigations. However, the molecular pathways related to its possible anti-inflammatory and antioxidant properties remain unclear.
View Article and Find Full Text PDFExpert Opin Ther Pat
January 2025
Department of Pharmaceutical and Biomedical Sciences, Rudolph H. Raabe College of Pharmacy, Ohio Northern University, Ada, OH, USA.
Introduction: Opioids have served as a cornerstone in pain management for decades. However, the emergence of increasingly potent synthetic analogs brings forth a range of side effects, including respiratory depression, tolerance, dependence, constipation, and, more importantly, the development of severe and debilitating opioid use disorder (OUD). Search for therapeutics to mitigate OUD has been challenging and this has called for novel approaches that include design of small molecules targeting neuronal circuits involved in addiction (opioid, dopamine, serotonin, norepinephrine, and glutamate receptors, etc.
View Article and Find Full Text PDFProbiotics Antimicrob Proteins
January 2025
Enzyme and Microbial Technology Research Center, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor, Malaysia.
The emergence of multidrug-resistant pathogens presents a significant global health challenge, which is primarily fuelled by overuse and misuse of antibiotics. Bacteria-derived antimicrobial metabolites offer a promising alternative strategy for combating antimicrobial resistance issues. Bacillus velezensis PD9 (BvPD9), isolated from stingless bee propolis, has been reported to have antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA).
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