Structural investigation of Trypanosoma cruzi Akt-like kinase as drug target against Chagas disease.
Akt/PKB
American trypanosomiasis
NMR
PH domain
Parasitic disease
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
02 05 2024
02 05 2024
Historique:
received:
19
01
2024
accepted:
12
04
2024
medline:
2
5
2024
pubmed:
2
5
2024
entrez:
1
5
2024
Statut:
epublish
Résumé
According to the World Health Organization, Chagas disease (CD) is the most prevalent poverty-promoting neglected tropical disease. Alarmingly, climate change is accelerating the geographical spreading of CD causative parasite, Trypanosoma cruzi, which additionally increases infection rates. Still, CD treatment remains challenging due to a lack of safe and efficient drugs. In this work, we analyze the viability of T. cruzi Akt-like kinase (TcAkt) as drug target against CD including primary structural and functional information about a parasitic Akt protein. Nuclear Magnetic Resonance derived information in combination with Molecular Dynamics simulations offer detailed insights into structural properties of the pleckstrin homology (PH) domain of TcAkt and its binding to phosphatidylinositol phosphate ligands (PIP). Experimental data combined with Alpha Fold proposes a model for the mechanism of action of TcAkt involving a PIP-induced disruption of the intramolecular interface between the kinase and the PH domain resulting in an open conformation enabling TcAkt kinase activity. Further docking experiments reveal that TcAkt is recognized by human inhibitors PIT-1 and capivasertib, and TcAkt inhibition by UBMC-4 and UBMC-6 is achieved via binding to TcAkt kinase domain. Our in-depth structural analysis of TcAkt reveals potential sites for drug development against CD, located at activity essential regions.
Identifiants
pubmed: 38693166
doi: 10.1038/s41598-024-59654-8
pii: 10.1038/s41598-024-59654-8
doi:
Substances chimiques
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Protozoan Proteins
0
Protein Kinase Inhibitors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
10039Subventions
Organisme : CIHR
ID : PJT-155941
Pays : Canada
Organisme : CIHR
ID : PJT-155941
Pays : Canada
Informations de copyright
© 2024. The Author(s).
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