6S9W
Crystal Structure of AKT1 in Complex with Covalent-Allosteric AKT Inhibitor 16a
Summary for 6S9W
| Entry DOI | 10.2210/pdb6s9w/pdb |
| Descriptor | RAC-alpha serine/threonine-protein kinase, ~{N}-[3-[1-[[4-(5-methyl-6-oxidanylidene-3-phenyl-1~{H}-pyrazin-2-yl)phenyl]methyl]piperidin-4-yl]-2-oxidanylidene-1~{H}-benzimidazol-5-yl]propanamide (3 entities in total) |
| Functional Keywords | akt1, akt2, akt3, borussertib, covalent-allosteric, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 52308.70 |
| Authors | Landel, I.,Mueller, M.P.,Rauh, D. (deposition date: 2019-07-15, release date: 2019-10-16, Last modification date: 2025-10-01) |
| Primary citation | Quambusch, L.,Landel, I.,Depta, L.,Weisner, J.,Uhlenbrock, N.,Muller, M.P.,Glanemann, F.,Althoff, K.,Siveke, J.T.,Rauh, D. Covalent-Allosteric Inhibitors to Achieve Akt Isoform-Selectivity. Angew.Chem.Int.Ed.Engl., 58:18823-18829, 2019 Cited by PubMed Abstract: Isoforms of protein kinase Akt are involved in essential processes including cell proliferation, survival, and metabolism. However, their individual roles in health and disease have not been thoroughly evaluated. Thus, there is an urgent need for perturbation studies, preferably mediated by highly selective bioactive small molecules. Herein, we present a structure-guided approach for the design of structurally diverse and pharmacologically beneficial covalent-allosteric modifiers, which enabled an investigation of the isoform-specific preferences and the important residues within the allosteric site of the different isoforms. The biochemical, cellular, and structural evaluations revealed interactions responsible for the selective binding profiles. The isoform-selective covalent-allosteric Akt inhibitors that emerged from this approach showed a conclusive structure-activity relationship and broke ground in the development of selective probes to delineate the isoform-specific functions of Akt kinases. PubMed: 31584233DOI: 10.1002/anie.201909857 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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