8X3M
Crystal structure of p38alpha with an allosteric inhibitor 2
Summary for 8X3M
| Entry DOI | 10.2210/pdb8x3m/pdb |
| Related | 7x4u |
| Descriptor | Mitogen-activated protein kinase 14, ~{N}-(5,6-dimethoxy-1,3-benzothiazol-2-yl)-2-[(4-fluoranylphenoxy)methyl]-1,3-thiazole-4-carboxamide (3 entities in total) |
| Functional Keywords | protein kinase mapk family allosteric inhibitor covalent bond, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 42200.14 |
| Authors | Hasegawa, S.,Kinoshita, T. (deposition date: 2023-11-14, release date: 2024-11-20, Last modification date: 2025-03-05) |
| Primary citation | Hasegawa, S.,Yoshida, M.,Nagao, H.,Sugiyama, H.,Sawa, M.,Kinoshita, T. Distinct binding modes of a benzothiazole derivative confer structural bases for increasing ERK2 or p38 alpha MAPK selectivity. Biochem.Biophys.Res.Commun., 704:149707-149707, 2024 Cited by PubMed Abstract: Mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase 2 (ERK2) and p38α MAP kinase (p38α MAPK), regulate various cellular responses. ERK2 is a drug target for treating many diseases, such as cancer, whereas p38α has attracted much attention as a promising drug target for treating inflammatory disorders. ERK2 is a critical off-target for p38α MAPK and vice versa. In this study, an allosteric ERK2 inhibitor with a benzothiazole moiety (compound 1) displayed comparable inhibitory activity against p38α MAPK. Crystal structures of these MAPKs showed that compound 1 bound to the allosteric site of ERK2 and p38α MAPK in distinct manners. Compound 1 formed a covalent bond with Cys162 of p38α MAPK, whereas this covalent bond was absent in the ERK2 complex even though the corresponding cysteine is conserved in ERK2. Structural dissection combined with computational simulations indicated that an amino acid difference in the allosteric site is responsible for the distinct binding modes of compound 1 with ERK2 and p38α MAPK. These structural insights underline the feasibility of developing highly selective and potent ERK2 and p38α MAPK inhibitors. PubMed: 38428305DOI: 10.1016/j.bbrc.2024.149707 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.85 Å) |
Structure validation
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