6S9W

Crystal Structure of AKT1 in Complex with Covalent-Allosteric AKT Inhibitor 16a

6S9W の概要

• エントリーDOI: 10.2210/pdb6s9w/pdb
• 分子名称: 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)
• 機能のキーワード: akt1, akt2, akt3, borussertib, covalent-allosteric, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 52308.70

構造登録者

Landel, I.,Mueller, M.P.,Rauh, D. (登録日: 2019-07-15, 公開日: 2019-10-16, 最終更新日: 2025-10-01)

主引用文献

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

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: 31584233
DOI: 10.1002/anie.201909857

実験手法

X-RAY DIFFRACTION (2.3 Å)