5zj6
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of HCK kinase complexed with a pyrrolo-pyrimidine inhibitor 7-[trans-4-(4-methylpiperazin-1-yl)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine== | |
| + | <StructureSection load='5zj6' size='340' side='right' caption='[[5zj6]], [[Resolution|resolution]] 1.70Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5zj6]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ZJ6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ZJ6 FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=VSE:7-[TRANS-4-(4-METHYLPIPERAZIN-1-YL)CYCLOHEXYL]-5-(4-PHENOXYPHENYL)-7H-PYRROLO[2,3-D]PYRIMIDIN-4-AMINE'>VSE</scene></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> | ||
| + | <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=5zj6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zj6 OCA], [http://pdbe.org/5zj6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5zj6 RCSB], [http://www.ebi.ac.uk/pdbsum/5zj6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5zj6 ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/HCK_HUMAN HCK_HUMAN]] Note=Aberrant activation of HCK by HIV-1 protein Nef enhances HIV-1 replication and contributes to HIV-1 pathogenicity.<ref>PMID:19114024</ref> <ref>PMID:20452982</ref> Note=Aberrant activation of HCK, e.g. by the BCR-ABL fusion protein, promotes cancer cell proliferation.<ref>PMID:19114024</ref> <ref>PMID:20452982</ref> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/HCK_HUMAN HCK_HUMAN]] Non-receptor tyrosine-protein kinase found in hematopoietic cells that transmits signals from cell surface receptors and plays an important role in the regulation of innate immune responses, including neutrophil, monocyte, macrophage and mast cell functions, phagocytosis, cell survival and proliferation, cell adhesion and migration. Acts downstream of receptors that bind the Fc region of immunoglobulins, such as FCGR1A and FCGR2A, but also CSF3R, PLAUR, the receptors for IFNG, IL2, IL6 and IL8, and integrins, such as ITGB1 and ITGB2. During the phagocytic process, mediates mobilization of secretory lysosomes, degranulation, and activation of NADPH oxidase to bring about the respiratory burst. Plays a role in the release of inflammatory molecules. Promotes reorganization of the actin cytoskeleton and actin polymerization, formation of podosomes and cell protrusions. Inhibits TP73-mediated transcription activation and TP73-mediated apoptosis. Phosphorylates CBL in response to activation of immunoglobulin gamma Fc region receptors. Phosphorylates ADAM15, BCR, ELMO1, FCGR2A, GAB1, GAB2, RAPGEF1, STAT5B, TP73, VAV1 and WAS.<ref>PMID:8132624</ref> <ref>PMID:7535819</ref> <ref>PMID:9406996</ref> <ref>PMID:9407116</ref> <ref>PMID:10092522</ref> <ref>PMID:10779760</ref> <ref>PMID:10973280</ref> <ref>PMID:12411494</ref> <ref>PMID:11741929</ref> <ref>PMID:11904303</ref> <ref>PMID:11896602</ref> <ref>PMID:15010462</ref> <ref>PMID:15952790</ref> <ref>PMID:15998323</ref> <ref>PMID:17535448</ref> <ref>PMID:17310994</ref> <ref>PMID:19114024</ref> <ref>PMID:19903482</ref> <ref>PMID:20452982</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Since phosphorylation is involved in various physiological events, kinases and interacting factors can be potential targets for drug discovery. For the development and improvement of inhibitors from the point of view of mechanistic enzymology, a cell-free protein synthesis system would be advantageous, since it could prepare mutant proteins easily. However, especially in the case of protein kinase, product solubility remains one of the major challenges. To overcome this problem, we prepared a chaperone-supplemented extract from Escherichia coli BL21cells harboring a plasmid encoding a set of chaperone genes, dnaK, dnaJ, and grpE. We explored cell-disruption procedures and constructed an efficient protein synthesis system. Employing this system, we produced the kinase domain of human hematopoietic cell kinase (HCK) to obtain further structural information about its molecular interaction with one of its inhibitors, previously developed by our group (RK-20449). Lower reaction temperature improved the solubility, and addition of a protein phosphatase (YpoH) facilitated the homogeneous production of the non-phosphorylated kinase domain. Crystals of the purified product were obtained and the kinase-inhibitor complex structure was solved at 1.7A resolution. In addition, results of kinase activity measurement, using a synthetic substrate, showed that the kinase activity was facilitated by autophosphorylation at Tyr416, as confirmed by the peptide mass mapping. | ||
| - | + | Phosphorylated and non-phosphorylated HCK kinase domains produced by cell-free protein expression.,Katsura K, Tomabechi Y, Matsuda T, Yonemochi M, Mikuni J, Ohsawa N, Terada T, Yokoyama S, Kukimoto-Niino M, Takemoto C, Shirouzu M Protein Expr Purif. 2018 May 21;150:92-99. doi: 10.1016/j.pep.2018.05.005. PMID:29793032<ref>PMID:29793032</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | [[Category: | + | <div class="pdbe-citations 5zj6" style="background-color:#fffaf0;"></div> |
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Non-specific protein-tyrosine kinase]] | ||
[[Category: Kukimoto-Niino, M]] | [[Category: Kukimoto-Niino, M]] | ||
[[Category: Shirouzu, M]] | [[Category: Shirouzu, M]] | ||
| + | [[Category: Tomabechi, Y]] | ||
| + | [[Category: Kinase/kinase inhibitor]] | ||
| + | [[Category: Transferase]] | ||
Revision as of 05:54, 6 June 2018
Crystal structure of HCK kinase complexed with a pyrrolo-pyrimidine inhibitor 7-[trans-4-(4-methylpiperazin-1-yl)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
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