6RNU
BCL-XL in a complex with a covalent small molecule inhibitor
Summary for 6RNU
| Entry DOI | 10.2210/pdb6rnu/pdb |
| Descriptor | Bcl-2-like protein 1, 4-(4-fluorophenyl)-3-fluorosulfonyl-benzoic acid, BROMIDE ION, ... (4 entities in total) |
| Functional Keywords | bcl-xl, signaling protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 41445.17 |
| Authors | Hargreaves, D. (deposition date: 2019-05-09, release date: 2019-10-02, Last modification date: 2024-11-20) |
| Primary citation | Mukherjee, H.,Su, N.,Belmonte, M.A.,Hargreaves, D.,Patel, J.,Tentarelli, S.,Aquila, B.,Grimster, N.P. Discovery and optimization of covalent Bcl-xL antagonists. Bioorg.Med.Chem.Lett., 29:126682-126682, 2019 Cited by PubMed Abstract: Over the last ten years, targeted covalent inhibition has become a key discipline within medicinal chemistry research, most notably in the development of oncology therapeutics. One area where this approach is underrepresented, however, is in targeting protein-protein interactions. This is primarily because these hydrophobic interfaces lack appropriately located cysteine residues to allow for standard conjugate addition chemistry. Herein, we report our development of the first covalent inhibitors of the antiapoptotic protein B-cell lymphoma extra-large (Bcl-xL), utilizing a sulfonyl fluoride (SF) warhead to selectively covalently modify tyrosine 101 of the BH3 domain-binding groove. These compounds display time-dependent inhibition in a biochemical assay and are cellularly active (U266B1). In addition, compound 7 was further elaborated to generate a chemical-biology probe molecule, which may find utility in understanding the intricacies of Bcl-xL biology. PubMed: 31606346DOI: 10.1016/j.bmcl.2019.126682 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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