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| | ==JAK1 kinase (JH1 domain) in complex with compound 72== | | ==JAK1 kinase (JH1 domain) in complex with compound 72== |
| - | <StructureSection load='4fk6' size='340' side='right' caption='[[4fk6]], [[Resolution|resolution]] 2.20Å' scene=''> | + | <StructureSection load='4fk6' size='340' side='right'caption='[[4fk6]], [[Resolution|resolution]] 2.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4fk6]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4FK6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4FK6 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4fk6]] 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=4FK6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4FK6 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0UJ:N-({1-[(1R,2R,4S)-BICYCLO[2.2.1]HEPT-2-YL]-1,6-DIHYDROIMIDAZO[4,5-D]PYRROLO[2,3-B]PYRIDIN-2-YL}METHYL)METHANESULFONAMIDE'>0UJ</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0UJ:N-({1-[(1R,2R,4S)-BICYCLO[2.2.1]HEPT-2-YL]-1,6-DIHYDROIMIDAZO[4,5-D]PYRROLO[2,3-B]PYRIDIN-2-YL}METHYL)METHANESULFONAMIDE'>0UJ</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</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=4fk6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fk6 OCA], [https://pdbe.org/4fk6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4fk6 RCSB], [https://www.ebi.ac.uk/pdbsum/4fk6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4fk6 ProSAT]</span></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4e4n|4e4n]], [[4e4l|4e4l]]</td></tr>
| + | |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">JAK1, JAK1A, JAK1B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></td></tr>
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| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4fk6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fk6 OCA], [http://pdbe.org/4fk6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4fk6 RCSB], [http://www.ebi.ac.uk/pdbsum/4fk6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4fk6 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/JAK1_HUMAN JAK1_HUMAN]] Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor. | + | [https://www.uniprot.org/uniprot/JAK1_HUMAN JAK1_HUMAN] Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Janus kinase|Janus kinase]] | + | *[[Janus kinase 3D structures|Janus kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Non-specific protein-tyrosine kinase]] | + | [[Category: Large Structures]] |
| - | [[Category: Eigenbrot, C]] | + | [[Category: Eigenbrot C]] |
| - | [[Category: Steffek, M]] | + | [[Category: Steffek M]] |
| - | [[Category: Phospho transfer]]
| + | |
| - | [[Category: Phospho tyrosine]]
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| - | [[Category: Protein kinase]]
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| - | [[Category: Transferase-transferase inhibitor complex]]
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| Structural highlights
Function
JAK1_HUMAN Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor.
Publication Abstract from PubMed
Herein we describe our successful efforts in obtaining C-2 substituted imidazo-pyrrolopyridines with improved JAK1 selectivity relative to JAK2 by targeting an amino acid residue that differs between the two isoforms (JAK1: E966; JAK2: D939). Efforts to improve cellular potency by reducing the polarity of the inhibitors are also detailed. The X-ray crystal structure of a representative inhibitor in complex with the JAK1 enzyme is also disclosed.
Structure-based discovery of C-2 substituted imidazo-pyrrolopyridine JAK1 inhibitors with improved selectivity over JAK2.,Labadie S, Dragovich PS, Barrett K, Blair WS, Bergeron P, Chang C, Deshmukh G, Eigenbrot C, Ghilardi N, Gibbons P, Hurley CA, Johnson A, Kenny JR, Kohli PB, Kulagowski JJ, Liimatta M, Lupardus PJ, Mendonca R, Murray JM, Pulk R, Shia S, Steffek M, Ubhayakar S, Ultsch M, van Abbema A, Ward S, Zak M Bioorg Med Chem Lett. 2012 Oct 11. pii: S0960-894X(12)01275-9. doi:, 10.1016/j.bmcl.2012.10.008. PMID:23107482[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Labadie S, Dragovich PS, Barrett K, Blair WS, Bergeron P, Chang C, Deshmukh G, Eigenbrot C, Ghilardi N, Gibbons P, Hurley CA, Johnson A, Kenny JR, Kohli PB, Kulagowski JJ, Liimatta M, Lupardus PJ, Mendonca R, Murray JM, Pulk R, Shia S, Steffek M, Ubhayakar S, Ultsch M, van Abbema A, Ward S, Zak M. Structure-based discovery of C-2 substituted imidazo-pyrrolopyridine JAK1 inhibitors with improved selectivity over JAK2. Bioorg Med Chem Lett. 2012 Oct 11. pii: S0960-894X(12)01275-9. doi:, 10.1016/j.bmcl.2012.10.008. PMID:23107482 doi:http://dx.doi.org/10.1016/j.bmcl.2012.10.008
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