View source for 9hhw


==Crystal structure of TTBK1 with a covalent compound GCL95==
<StructureSection load='9hhw' size='340' side='right'caption='[[9hhw]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9hhw]] is a 1 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=9HHW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9HHW FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1IU7:~{N}-[2-(1~{H}-pyrrolo[2,3-b]pyridin-5-yl)phenyl]propanamide'>A1IU7</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=9hhw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9hhw OCA], [https://pdbe.org/9hhw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9hhw RCSB], [https://www.ebi.ac.uk/pdbsum/9hhw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9hhw ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/TTBK1_HUMAN TTBK1_HUMAN] Serine/threonine kinase which is able to phosphorylate TAU on serine, threonine and tyrosine residues. Induces aggregation of TAU.<ref>PMID:16923168</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Protein kinases are important drug targets, yet specific inhibitors have been developed for only a fraction of the more than 500 human kinases. A major challenge in designing inhibitors for highly related kinases is selectivity. Unlike their non-covalent counterparts, covalent inhibitors offer the advantage of selectively targeting structurally similar kinases by modifying specific protein side chains, particularly non-conserved cysteines. Previously, covalent fragment screens yielded potent and selective compounds for individual kinases such as ERK1/2 but have not been applied to the broader kinome. Furthermore, many of the accessible cysteine positions have not been addressed so far. Here, we outline a generalizable approach to sample ATP-site cysteines with fragment-like covalent inhibitors. We present the development of a kinase-focused fragment library and its systematic screening against a curated selection of 47 kinases, with 60 active site-proximal cysteines using LC/MS and differential scanning fluorimetry (DSF) assays, followed by hit validation through various complementary techniques. Our findings expand the repertoire of targetable cysteines within protein kinases, provide insight into unique binding modes identified from crystal structures and deliver isoform-specific hits with promising profiles as starting points for the development of highly potent and selective covalent inhibitors.

Probing the Protein Kinases' Cysteinome by Covalent Fragments.,Wang G, Seidler NJ, Rohm S, Pan Y, Liang XJ, Haarer L, Berger BT, Sivashanmugam SA, Wydra VR, Forster M, Laufer SA, Chaikuad A, Gehringer M, Knapp S Angew Chem Int Ed Engl. 2024 Dec 24:e202419736. doi: 10.1002/anie.202419736. PMID:39716901<ref>PMID:39716901</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9hhw" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Gehringer M]]
[[Category: Knapp S]]
[[Category: Seidler N]]
[[Category: Wang G]]