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| | ==Crystal structures of JAK1 and JAK2 inhibitor complexes== | | ==Crystal structures of JAK1 and JAK2 inhibitor complexes== |
| - | <StructureSection load='3eyg' size='340' side='right' caption='[[3eyg]], [[Resolution|resolution]] 1.90Å' scene=''> | + | <StructureSection load='3eyg' size='340' side='right'caption='[[3eyg]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3eyg]] is a 1 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=3EYG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3EYG FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3eyg]] 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=3EYG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3EYG FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MI1:3-{(3R,4R)-4-METHYL-3-[METHYL(7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)AMINO]PIPERIDIN-1-YL}-3-OXOPROPANENITRILE'>MI1</scene></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]] 1.9Å</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MI1:3-{(3R,4R)-4-METHYL-3-[METHYL(7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)AMINO]PIPERIDIN-1-YL}-3-OXOPROPANENITRILE'>MI1</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3eyh|3eyh]]</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=3eyg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3eyg OCA], [https://pdbe.org/3eyg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3eyg RCSB], [https://www.ebi.ac.uk/pdbsum/3eyg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3eyg ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">JAK1, hCG_22179 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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| - | <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=3eyg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3eyg OCA], [http://pdbe.org/3eyg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3eyg RCSB], [http://www.ebi.ac.uk/pdbsum/3eyg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3eyg 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. |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | <jmolCheckbox> | | <jmolCheckbox> |
| | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ey/3eyg_consurf.spt"</scriptWhenChecked> | | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ey/3eyg_consurf.spt"</scriptWhenChecked> |
| - | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </jmolCheckbox> |
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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: Bamert, R S]] | + | [[Category: Bamert RS]] |
| - | [[Category: Fantino, E]] | + | [[Category: Fantino E]] |
| - | [[Category: Patell, O]] | + | [[Category: Patell O]] |
| - | [[Category: Walden, P M]] | + | [[Category: Walden PM]] |
| - | [[Category: Wang, C]] | + | [[Category: Wang C]] |
| - | [[Category: Williams, N K]] | + | [[Category: Williams NK]] |
| - | [[Category: Atp-binding]]
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| - | [[Category: Jak kinase]]
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| - | [[Category: Kinase]]
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| - | [[Category: Nucleotide-binding]]
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| - | [[Category: Phosphoprotein]]
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| - | [[Category: Sh2 domain]]
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| - | [[Category: Transferase]]
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| - | [[Category: Tyrosine-protein kinase]]
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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.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The Janus kinases (JAKs) are a pivotal family of protein tyrosine kinases (PTKs) that play prominent roles in numerous cytokine signaling pathways, with aberrant JAK activity associated with a variety of hematopoietic malignancies, cardiovascular diseases and immune-related disorders. Whereas the structures of the JAK2 and JAK3 PTK domains have been determined, the structure of the JAK1 PTK domain is unknown. Here, we report the high-resolution crystal structures of the "active form" of the JAK1 PTK domain in complex with two JAK inhibitors, a tetracyclic pyridone 2-t-butyl-9-fluoro-3,6-dihydro-7H-benz[h]-imidaz[4,5-f]isoquinoline-7-one (CMP6) and (3R,4R)-3-[4-methyl-3-[N-methyl-N-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]p iperidin-1-yl]-3-oxopropionitrile (CP-690,550), and compare them with the corresponding JAK2 PTK inhibitor complexes. Both inhibitors bound in a similar manner to JAK1, namely buried deep within a constricted ATP-binding site, thereby providing a basis for the potent inhibition of JAK1. As expected, the mode of inhibitor binding in JAK1 was very similar to that observed in JAK2, highlighting the challenges in developing JAK-specific inhibitors that target the ATP-binding site. Nevertheless, differences surrounding the JAK1 and JAK2 ATP-binding sites were apparent, thereby providing a platform for the rational design of JAK2- and JAK1-specific inhibitors.
Dissecting specificity in the Janus kinases: the structures of JAK-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains.,Williams NK, Bamert RS, Patel O, Wang C, Walden PM, Wilks AF, Fantino E, Rossjohn J, Lucet IS J Mol Biol. 2009 Mar 20;387(1):219-32. Epub 2009 Jan 29. PMID:19361440[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Williams NK, Bamert RS, Patel O, Wang C, Walden PM, Wilks AF, Fantino E, Rossjohn J, Lucet IS. Dissecting specificity in the Janus kinases: the structures of JAK-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains. J Mol Biol. 2009 Mar 20;387(1):219-32. Epub 2009 Jan 29. PMID:19361440 doi:http://dx.doi.org/10.1016/j.jmb.2009.01.041
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