7NH5

Co-Crystal Structure of Akt1 in Complex with Covalent-Allosteric Akt Inhibitor 6

7NH5 の概要

• エントリーDOI: 10.2210/pdb7nh5/pdb
• 分子名称: RAC-alpha serine/threonine-protein kinase, ACETATE ION, ~{N}-methyl-6-[4-[[4-[2-oxidanylidene-6-(propanoylamino)-3~{H}-benzimidazol-1-yl]piperidin-1-yl]methyl]phenyl]-5-phenyl-pyridine-3-carboxamide, ... (4 entities in total)
• 機能のキーワード: akt1, akt2, akt3, 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: 52393.78

構造登録者

Landel, I.,Mueller, M.P.,Rauh, D. (登録日: 2021-02-10, 公開日: 2021-09-08, 最終更新日: 2024-01-31)

主引用文献

Quambusch, L.,Depta, L.,Landel, I.,Lubeck, M.,Kirschner, T.,Nabert, J.,Uhlenbrock, N.,Weisner, J.,Kostka, M.,Levy, L.M.,Schultz-Fademrecht, C.,Glanemann, F.,Althoff, K.,Muller, M.P.,Siveke, J.T.,Rauh, D.
Cellular model system to dissect the isoform-selectivity of Akt inhibitors.
Nat Commun, 12:5297-5297, 2021

PubMed Abstract: The protein kinase Akt plays a pivotal role in cellular processes. However, its isoforms' distinct functions have not been resolved to date, mainly due to the lack of suitable biochemical and cellular tools. Against this background, we present the development of an isoform-dependent Ba/F3 model system to translate biochemical results on isoform specificity to the cellular level. Our cellular model system complemented by protein X-ray crystallography and structure-based ligand design results in covalent-allosteric Akt inhibitors with unique selectivity profiles. In a first proof-of-concept, the developed molecules allow studies on isoform-selective effects of Akt inhibition in cancer cells. Thus, this study will pave the way to resolve isoform-selective roles in health and disease and foster the development of next-generation therapeutics with superior on-target properties.

PubMed: 34489430
DOI: 10.1038/s41467-021-25512-8

実験手法

X-RAY DIFFRACTION (1.9 Å)