7Q8Z

Crystal structure of TTBK2 in complex with VNG1.33 (compound 27)

7Q8Z の概要

• エントリーDOI: 10.2210/pdb7q8z/pdb
• 分子名称: Tau-tubulin kinase 2, PHOSPHATE ION, ~{N}-(4-phenoxyphenyl)-7~{H}-pyrrolo[2,3-d]pyrimidin-4-amine, ... (4 entities in total)
• 機能のキーワード: kinase, ttbk2, tau tubulin kinase, kinase inhibitor, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 69919.99

構造登録者

Chaikuad, A.,Nozal, V.,Martinez, A.,Knapp, S.,Structural Genomics Consortium (SGC) (登録日: 2021-11-11, 公開日: 2022-03-09, 最終更新日: 2024-01-31)

主引用文献

Nozal, V.,Martinez-Gonzalez, L.,Gomez-Almeria, M.,Gonzalo-Consuegra, C.,Santana, P.,Chaikuad, A.,Perez-Cuevas, E.,Knapp, S.,Lietha, D.,Ramirez, D.,Petralla, S.,Monti, B.,Gil, C.,Martin-Requero, A.,Palomo, V.,de Lago, E.,Martinez, A.
TDP-43 Modulation by Tau-Tubulin Kinase 1 Inhibitors: A New Avenue for Future Amyotrophic Lateral Sclerosis Therapy.
J.Med.Chem., 65:1585-1607, 2022

PubMed Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease without any effective treatment. Protein TDP-43 is a pathological hallmark of ALS in both sporadic and familiar patients. Post-translational modifications of TDP-43 promote its aggregation in the cytoplasm. Tau-Tubulin kinase (TTBK1) phosphorylates TDP-43 in cellular and animal models; thus, TTBK1 inhibitors emerge as a promising therapeutic strategy for ALS. The design, synthesis, biological evaluation, kinase-ligand complex structure determination, and molecular modeling studies confirmed novel pyrrolopyrimidine derivatives as valuable inhibitors for further development. Moreover, compound revealed good brain penetration and was able to reduce TDP-43 phosphorylation not only in cell cultures but also in the spinal cord of transgenic TDP-43 mice. A shift to M2 anti-inflammatory microglia was also demonstrated . Both these activities led to motor neuron preservation in mice, proposing pyrrolopyrimidine as a valuable lead compound for future ALS therapy.

PubMed: 34978799
DOI: 10.1021/acs.jmedchem.1c01942

実験手法

X-RAY DIFFRACTION (1.57 Å)