7Q8Z
Crystal structure of TTBK2 in complex with VNG1.33 (compound 27)
Summary for 7Q8Z
| Entry DOI | 10.2210/pdb7q8z/pdb |
| Descriptor | Tau-tubulin kinase 2, PHOSPHATE ION, ~{N}-(4-phenoxyphenyl)-7~{H}-pyrrolo[2,3-d]pyrimidin-4-amine, ... (4 entities in total) |
| Functional Keywords | kinase, ttbk2, tau tubulin kinase, kinase inhibitor, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 69919.99 |
| Authors | Chaikuad, A.,Nozal, V.,Martinez, A.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2021-11-11, release date: 2022-03-09, Last modification date: 2024-01-31) |
| Primary citation | 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 Cited by 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: 34978799DOI: 10.1021/acs.jmedchem.1c01942 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.57 Å) |
Structure validation
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