6HHJ

Crystal Structure of AKT1 in Complex with Covalent-Allosteric AKT Inhibitor 24b

6HHJ の概要

• エントリーDOI: 10.2210/pdb6hhj/pdb
• 分子名称: RAC-alpha serine/threonine-protein kinase, ~{N}-[1-methyl-2-oxidanylidene-3-[1-[[4-(5-oxidanylidene-3-phenyl-6~{H}-1,6-naphthyridin-2-yl)phenyl]methyl]piperidin-4-yl]benzimidazol-5-yl]propanamide (3 entities in total)
• 機能のキーワード: akt1, 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: 52358.76

構造登録者

Landel, I.,Weisner, J.,Mueller, M.P.,Scheinpflug, R.,Rauh, D. (登録日: 2018-08-28, 公開日: 2019-02-20, 最終更新日: 2024-11-13)

主引用文献

Uhlenbrock, N.,Smith, S.,Weisner, J.,Landel, I.,Lindemann, M.,Le, T.A.,Hardick, J.,Gontla, R.,Scheinpflug, R.,Czodrowski, P.,Janning, P.,Depta, L.,Quambusch, L.,Muller, M.P.,Engels, B.,Rauh, D.
Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt.
Chem Sci, 10:3573-3585, 2019

PubMed Abstract: The Ser/Thr kinase Akt (Protein Kinase B/PKB) is a master switch in cellular signal transduction pathways. Its downstream signaling influences cell proliferation, cell growth, and apoptosis, rendering Akt a prominent drug target. The unique activation mechanism of Akt involves a change of the relative orientation of its N-terminal pleckstrin homology (PH) and the kinase domain and makes this kinase suitable for highly specific allosteric modulation. Here we present a unique set of crystal structures of covalent-allosteric interdomain inhibitors in complex with full-length Akt and report the structure-based design, synthesis, biological and pharmacological evaluation of a focused library of these innovative inhibitors.

PubMed: 30996949
DOI: 10.1039/c8sc05212c

実験手法

X-RAY DIFFRACTION (2.3 Å)