Summary for 9EFJ
| Entry DOI | 10.2210/pdb9efj/pdb |
| Descriptor | Induced myeloid leukemia cell differentiation protein Mcl-1, (1R)-N-{5-[(dihydroxy-lambda~4~-sulfanyl)oxy]pyridin-3-yl}-2,3-dihydro-1H-indene-1-carboxamide (3 entities in total) |
| Functional Keywords | histidine-covalent stapled alpha-helical peptides, apoptosis |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 17771.20 |
| Authors | Muzzarelli, K.M.,Assar, Z.,Udompholkul, P.,Pellecchia, M.,Baggio, C.,Prentiss, A.M. (deposition date: 2024-11-20, release date: 2025-11-19, Last modification date: 2025-11-26) |
| Primary citation | Alboreggia, G.,Muzzarelli, K.,Assar, Z.,Pellecchia, M. A Fragment-Based Electrophile-First Approach to Target Histidine with Aryl-Fluorosulfates: Application to hMcl-1. J.Med.Chem., 2025 Cited by PubMed Abstract: Aryl-fluorosulfates are mild electrophiles that are very stable in biological media and in vivo and can efficiently react with the side chains of Lys, Tyr, or His residues, when properly juxtaposed by a high-affinity ligand. A more powerful approach to derive novel ligands would consist of starting from the covalent adduct and building the ligand off those initial interactions. While this strategy has been proven for Cys with molecular fragments containing Cys targeting electrophiles such as acrylamides, a corresponding strategy with fluorosulfates targeting His/Lys/Tyr residues has yet to be reported. We report here that a fragment library of aryl-fluorosulfates, when deployed with proper biophysical screening strategies, can identify initial covalent fragments. We report on novel strategies to enhance the success rate of such electrophile-based fragment screening for His/Lys/Tyr residues and to characterize the resulting hits. As an application, we report on novel covalent fragment hits targeting hMcl-1 His 224. PubMed: 41223148DOI: 10.1021/acs.jmedchem.5c02199 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.82 Å) |
Structure validation
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