8OZZ
PH domain of AKT-like kinase in Trypanosoma cruzi
Summary for 8OZZ
| Entry DOI | 10.2210/pdb8ozz/pdb |
| NMR Information | BMRB: 52088 |
| Descriptor | PH domain of Akt-like kinase in Trypanosoma cruzi (1 entity in total) |
| Functional Keywords | ph domain, akt-like/rac/pkb, kinase, trypanosoma cruzi, lipid binding protein |
| Biological source | Trypanosoma cruzi |
| Total number of polymer chains | 1 |
| Total formula weight | 13494.11 |
| Authors | Stadler, K.A.,Ortiz-Joya, L.J.,Zangger, K.,Gubensaek, N. (deposition date: 2023-05-09, release date: 2024-05-08) |
| Primary citation | Stadler, K.A.,Ortiz-Joya, L.J.,Singh Sahrawat, A.,Buhlheller, C.,Gruber, K.,Pavkov-Keller, T.,O'Hagan, T.B.,Guarne, A.,Pulido, S.,Marin-Villa, M.,Zangger, K.,Gubensak, N. Structural investigation of Trypanosoma cruzi Akt-like kinase as drug target against Chagas disease. Sci Rep, 14:10039-10039, 2024 Cited by PubMed Abstract: 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. PubMed: 38693166DOI: 10.1038/s41598-024-59654-8 PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
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