9Z3V
Histidine-covalent 165G1 targeting hMcl-1
This is a non-PDB format compatible entry.
Replaces: 9CKNSummary for 9Z3V
| Entry DOI | 10.2210/pdb9z3v/pdb |
| Descriptor | Induced myeloid leukemia cell differentiation protein Mcl-1, 165G1 (3 entities in total) |
| Functional Keywords | histidine-covalent stapled alpha-helical peptides, apoptosis |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 38730.21 |
| Authors | Alboreggia, G.,Atienza, E.,Muzzarelli, K.M.,Assar, Z.,Pellecchia, M. (deposition date: 2025-11-07, release date: 2026-05-13, Last modification date: 2026-05-27) |
| Primary citation | Alboreggia, G.,Atienza, E.L.,Muzzarelli, K.,Assar, Z.,Pellecchia, M. Covalent Targeting of Histidine Residues: A Ligand-First Approach. J.Med.Chem., 69:10201-10212, 2026 Cited by PubMed Abstract: The design of irreversible drugs has resulted, over the past decade, in several new therapeutics in oncology that present improved pharmacodynamic and pharmaconetic properties compared to reversible ligands. Nevertheless, most ligands to date are designed to target a cysteine (Cys) residue, which is not a very common amino acid and only rarely occurs in protein target binding sites, thereby limiting the applicability of this covalent targeting approach. Recent work from our laboratory and others suggests that, after Cys, histidine (His) residues can be particularly suitable for covalent substitution with proper electrophiles. Using a ligand-first, structure-based approach, we assessed the possibility of using different electrophiles including acrylamides, chloroacetamides, or aryl fluorosulfates to target His residues covalently. Targeting His224 of hMcl-1 with model peptides, we demonstrate that both aryl fluorosulfates and chloroacetamides can be used to target His residues efficiently. Our studies also report strategies and biophysical approaches useful for the design and characterization of such His-covalent agents. PubMed: 42054250DOI: 10.1021/acs.jmedchem.5c03255 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.6 Å) |
Structure validation
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