8OZZ

PH domain of AKT-like kinase in Trypanosoma cruzi

8OZZ の概要

• エントリーDOI: 10.2210/pdb8ozz/pdb
• NMR情報: BMRB: 52088
• 分子名称: PH domain of Akt-like kinase in Trypanosoma cruzi (1 entity in total)
• 機能のキーワード: ph domain, akt-like/rac/pkb, kinase, trypanosoma cruzi, lipid binding protein
• 由来する生物種: Trypanosoma cruzi
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 13494.11

構造登録者

Stadler, K.A.,Ortiz-Joya, L.J.,Zangger, K.,Gubensaek, N. (登録日: 2023-05-09, 公開日: 2024-05-08)

主引用文献

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

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: 38693166
DOI: 10.1038/s41598-024-59654-8

実験手法

SOLUTION NMR