5LWN
Crystal structure of JAK3 in complex with Compound 5 (FM409)
Summary for 5LWN
| Entry DOI | 10.2210/pdb5lwn/pdb |
| Descriptor | Tyrosine-protein kinase JAK3, 1-phenylurea, 1,2-ETHANEDIOL, ... (6 entities in total) |
| Functional Keywords | transferase, jak3, covalent inhibitor, reversible covalent inhibitor, induced pocket, arginine pocket, structural genomics, structural genomics consortium, sgc |
| Biological source | Homo sapiens (Human) |
| Cellular location | Endomembrane system ; Peripheral membrane protein : P52333 |
| Total number of polymer chains | 1 |
| Total formula weight | 34812.88 |
| Authors | Chaikuad, A.,Forster, M.,Mukhopadhyay, S.,Kupinska, K.,Ellis, K.,Mahajan, P.,Burgess-Brown, N.,Edwards, A.M.,Arrowsmith, C.H.,Bountra, C.,Laufer, S.A.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2016-09-18, release date: 2016-10-26, Last modification date: 2024-11-13) |
| Primary citation | Forster, M.,Chaikuad, A.,Bauer, S.M.,Holstein, J.,Robers, M.B.,Corona, C.R.,Gehringer, M.,Pfaffenrot, E.,Ghoreschi, K.,Knapp, S.,Laufer, S.A. Selective JAK3 Inhibitors with a Covalent Reversible Binding Mode Targeting a New Induced Fit Binding Pocket. Cell Chem Biol, 23:1335-1340, 2016 Cited by PubMed Abstract: Janus kinases (JAKs) are a family of cytoplasmatic tyrosine kinases that are attractive targets for the development of anti-inflammatory drugs given their roles in cytokine signaling. One question regarding JAKs and their inhibitors that remains under intensive debate is whether JAK inhibitors should be isoform selective. Since JAK3 functions are restricted to immune cells, an isoform-selective inhibitor for JAK3 could be especially valuable to achieve clinically more useful and precise effects. However, the high degree of structural conservation makes isoform-selective targeting a challenging task. Here, we present picomolar inhibitors with unprecedented kinome-wide selectivity for JAK3. Selectivity was achieved by concurrent covalent reversible targeting of a JAK3-specific cysteine residue and a ligand-induced binding pocket. We confirmed that in vitro activity and selectivity translate well into the cellular environment and suggest that our inhibitors are powerful tools to elucidate JAK3-specific functions. PubMed: 27840070DOI: 10.1016/j.chembiol.2016.10.008 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.6 Å) |
Structure validation
Download full validation report
