7NH4

Co-Crystal Structure of Akt1 in Complex with Covalent-Allosteric Akt Inhibitor 3

Summary for 7NH4

• Entry DOI: 10.2210/pdb7nh4/pdb
• Descriptor: RAC-alpha serine/threonine-protein kinase, ~{N}-[3-[1-[[4-[5-(hydroxymethyl)-3-phenyl-pyridin-2-yl]phenyl]methyl]piperidin-4-yl]-2-oxidanylidene-1~{H}-benzimidazol-5-yl]propanamide, ACETATE ION, ... (4 entities in total)
• Functional Keywords: akt1, akt2, akt3, covalent-allosteric, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 52425.80

Authors

Landel, I.,Mueller, M.P.,Rauh, D. (deposition date: 2021-02-10, release date: 2021-09-08, Last modification date: 2024-01-31)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.3 Å)