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| | ==Complex structure of cyclin G-associated kinase with gefitinib== | | ==Complex structure of cyclin G-associated kinase with gefitinib== |
| - | <StructureSection load='5y7z' size='340' side='right' caption='[[5y7z]], [[Resolution|resolution]] 2.80Å' scene=''> | + | <StructureSection load='5y7z' size='340' side='right'caption='[[5y7z]], [[Resolution|resolution]] 2.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5y7z]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Camelus_glama Camelus glama] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5Y7Z OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5Y7Z FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5y7z]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Lama_glama Lama glama]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5Y7Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5Y7Z FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=IRE:GEFITINIB'>IRE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.804Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GAK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IRE:GEFITINIB'>IRE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></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=5y7z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5y7z OCA], [https://pdbe.org/5y7z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5y7z RCSB], [https://www.ebi.ac.uk/pdbsum/5y7z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5y7z ProSAT]</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=5y7z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5y7z OCA], [http://pdbe.org/5y7z PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5y7z RCSB], [http://www.ebi.ac.uk/pdbsum/5y7z PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5y7z ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GAK_HUMAN GAK_HUMAN]] Associates with cyclin G and CDK5. Seems to act as an auxilin homolog that is involved in the uncoating of clathrin-coated vesicles by Hsc70 in non-neuronal cells. Expression oscillates slightly during the cell cycle, peaking at G1.<ref>PMID:10625686</ref> | + | [https://www.uniprot.org/uniprot/GAK_HUMAN GAK_HUMAN] Associates with cyclin G and CDK5. Seems to act as an auxilin homolog that is involved in the uncoating of clathrin-coated vesicles by Hsc70 in non-neuronal cells. Expression oscillates slightly during the cell cycle, peaking at G1.<ref>PMID:10625686</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Camelus glama]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Lama glama]] |
| - | [[Category: Non-specific serine/threonine protein kinase]] | + | [[Category: Large Structures]] |
| - | [[Category: Kato-Murayama, M]] | + | [[Category: Kato-Murayama M]] |
| - | [[Category: Murayama, K]] | + | [[Category: Murayama K]] |
| - | [[Category: Ohbayashi, N]] | + | [[Category: Ohbayashi N]] |
| - | [[Category: Shirouzu, M]] | + | [[Category: Shirouzu M]] |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Kinase]]
| + | |
| - | [[Category: Transferase-immune system complex]]
| + | |
| Structural highlights
Function
GAK_HUMAN Associates with cyclin G and CDK5. Seems to act as an auxilin homolog that is involved in the uncoating of clathrin-coated vesicles by Hsc70 in non-neuronal cells. Expression oscillates slightly during the cell cycle, peaking at G1.[1]
Publication Abstract from PubMed
Gefitinib is the molecular target drug for advanced non-small-cell lung cancer. The primary target of gefitinib is the positive mutation of epidermal growth factor receptor, but it also inhibits cyclin G-associated kinase (GAK). To reveal the molecular bases of GAK and gefitinib binding, structure analyses were conducted and determined two forms of the gefitinib-bound nanobodyGAK kinase domain complex structures. The first form, GAK_1, has one gefitinib at the ATP binding pocket, whereas the second form, GAK_2, binds one each in the ATP binding site and a novel binding site adjacent to the activation segment C-terminal helix, a unique element of the Numb-associated kinase family. In the novel binding site, gefitinib binds in the hydrophobic groove around the activation segment, disrupting the conserved hydrogen bonds for the catalytic activity. These structures suggest possibilities for the development of selective GAK inhibitors for viral infections, such as the hepatitis C virus.
Structural Basis for the Inhibition of Cyclin G-Associated Kinase by Gefitinib.,Ohbayashi N, Murayama K, Kato-Murayama M, Kukimoto-Niino M, Uejima T, Matsuda T, Ohsawa N, Yokoyoma S, Nojima H, Shirouzu M ChemistryOpen. 2018 Sep 10;7(9):721-727. doi: 10.1002/open.201800177. eCollection, 2018 Sep. PMID:30214852[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Greener T, Zhao X, Nojima H, Eisenberg E, Greene LE. Role of cyclin G-associated kinase in uncoating clathrin-coated vesicles from non-neuronal cells. J Biol Chem. 2000 Jan 14;275(2):1365-70. PMID:10625686
- ↑ Ohbayashi N, Murayama K, Kato-Murayama M, Kukimoto-Niino M, Uejima T, Matsuda T, Ohsawa N, Yokoyoma S, Nojima H, Shirouzu M. Structural Basis for the Inhibition of Cyclin G-Associated Kinase by Gefitinib. ChemistryOpen. 2018 Sep 10;7(9):721-727. doi: 10.1002/open.201800177. eCollection, 2018 Sep. PMID:30214852 doi:http://dx.doi.org/10.1002/open.201800177
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