7q8z
From Proteopedia
(Difference between revisions)
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==Crystal structure of TTBK2 in complex with VNG1.33 (compound 27)== | ==Crystal structure of TTBK2 in complex with VNG1.33 (compound 27)== | ||
| - | <StructureSection load='7q8z' size='340' side='right'caption='[[7q8z]]' scene=''> | + | <StructureSection load='7q8z' size='340' side='right'caption='[[7q8z]], [[Resolution|resolution]] 1.57Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7Q8Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7Q8Z FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7q8z]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7Q8Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7Q8Z FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7q8z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7q8z OCA], [https://pdbe.org/7q8z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7q8z RCSB], [https://www.ebi.ac.uk/pdbsum/7q8z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7q8z ProSAT]</span></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.57Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9IK:~{N}-(4-phenoxyphenyl)-7~{H}-pyrrolo[2,3-d]pyrimidin-4-amine'>9IK</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7q8z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7q8z OCA], [https://pdbe.org/7q8z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7q8z RCSB], [https://www.ebi.ac.uk/pdbsum/7q8z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7q8z ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Disease == | ||
| + | [https://www.uniprot.org/uniprot/TTBK2_HUMAN TTBK2_HUMAN] Spinocerebellar ataxia type 11. The disease is caused by mutations affecting the gene represented in this entry. | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/TTBK2_HUMAN TTBK2_HUMAN] Serine/threonine kinase that acts as a key regulator of ciliogenesis: controls the initiation of ciliogenesis by binding to the distal end of the basal body and promoting the removal of CCP110, which caps the mother centriole, leading to the recruitment of IFT proteins, which build the ciliary axoneme. Has some substrate preference for proteins that are already phosphorylated on a Tyr residue at the +2 position relative to the phosphorylation site. Able to phosphorylate tau on serines in vitro.<ref>PMID:21548880</ref> <ref>PMID:23141541</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | 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 29 revealed good brain penetration in vivo 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 in vivo. Both these activities led to motor neuron preservation in mice, proposing pyrrolopyrimidine 29 as a valuable lead compound for future ALS therapy. | ||
| + | |||
| + | TDP-43 Modulation by Tau-Tubulin Kinase 1 Inhibitors: A New Avenue for Future Amyotrophic Lateral Sclerosis Therapy.,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 J Med Chem. 2022 Jan 27;65(2):1585-1607. doi: 10.1021/acs.jmedchem.1c01942. Epub , 2022 Jan 3. PMID:34978799<ref>PMID:34978799</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7q8z" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Chaikuad A]] | [[Category: Chaikuad A]] | ||
Current revision
Crystal structure of TTBK2 in complex with VNG1.33 (compound 27)
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