4id7
From Proteopedia
(Difference between revisions)
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| - | [[ | + | ==ACK1 kinase in complex with the inhibitor cis-3-[8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl]cyclobutanol== |
| + | <StructureSection load='4id7' size='340' side='right' caption='[[4id7]], [[Resolution|resolution]] 3.00Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4id7]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4ID7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ID7 FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1G0:CIS-3-[8-AMINO-1-(4-PHENOXYPHENYL)IMIDAZO[1,5-A]PYRAZIN-3-YL]CYCLOBUTANOL'>1G0</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | ||
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ACK1, TNK2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=4id7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4id7 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4id7 RCSB], [http://www.ebi.ac.uk/pdbsum/4id7 PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/ACK1_HUMAN ACK1_HUMAN]] Non-receptor tyrosine-protein and serine/threonine-protein kinase that is implicated in cell spreading and migration, cell survival, cell growth and proliferation. Transduces extracellular signals to cytosolic and nuclear effectors. Phosphorylates AKT1, AR, MCF2, WASL and WWOX. Implicated in trafficking and clathrin-mediated endocytosis through binding to epidermal growth factor receptor (EGFR) and clathrin. Binds to both poly- and mono-ubiquitin and regulates ligand-induced degradation of EGFR, thereby contributing to the accumulation of EGFR at the limiting membrane of early endosomes. Downstream effector of CDC42 which mediates CDC42-dependent cell migration via phosphorylation of BCAR1. May be involved both in adult synaptic function and plasticity and in brain development. Activates AKT1 by phosphorylating it on 'Tyr-176'. Phosphorylates AR on 'Tyr-267' and 'Tyr-363' thereby promoting its recruitment to androgen-responsive enhancers (AREs). Phosphorylates WWOX on 'Tyr-287'. Phosphorylates MCF2, thereby enhancing its activity as a guanine nucleotide exchange factor (GEF) toward Rho family proteins. Contributes to the control of AXL receptor levels. Confers metastatic properties on cancer cells and promotes tumor growth by negatively regulating tumor suppressor such as WWOX and positively regulating pro-survival factors such as AKT1 and AR.<ref>PMID:10652228</ref> <ref>PMID:11278436</ref> <ref>PMID:16257963</ref> <ref>PMID:16247015</ref> <ref>PMID:17038317</ref> <ref>PMID:16472662</ref> <ref>PMID:18435854</ref> <ref>PMID:18262180</ref> <ref>PMID:19815557</ref> <ref>PMID:20383201</ref> <ref>PMID:20333297</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | This Letter describes the medicinal chemistry effort towards a series of novel imidazo[1,5-a]pyrazine derived inhibitors of ACK1. Virtual screening led to the discovery of the initial hit, and subsequent exploration of structure-activity relationships and optimization of drug metabolism and pharmacokinetic properties led to the identification of potent, selective and orally bioavailable ACK1 inhibitors. | ||
| - | + | Discovery of potent, selective and orally bioavailable imidazo[1,5-a]pyrazine derived ACK1 inhibitors.,Jin M, Wang J, Kleinberg A, Kadalbajoo M, Siu KW, Cooke A, Bittner MA, Yao Y, Thelemann A, Ji Q, Bhagwat S, Mulvihill KM, Rechka JA, Pachter JA, Crew AP, Epstein D, Mulvihill MJ Bioorg Med Chem Lett. 2013 Feb 15;23(4):979-84. doi: 10.1016/j.bmcl.2012.12.042. , Epub 2012 Dec 21. PMID:23317569<ref>PMID:23317569</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | == References == | |
| - | + | <references/> | |
| - | == | + | __TOC__ |
| - | + | </StructureSection> | |
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
| - | [[Category: Bhagwat, S | + | [[Category: Bhagwat, S]] |
| - | [[Category: Bittner, M | + | [[Category: Bittner, M]] |
| - | [[Category: Cooke, A | + | [[Category: Cooke, A]] |
| - | [[Category: Crew, A P | + | [[Category: Crew, A P]] |
| - | [[Category: Epstein, D | + | [[Category: Epstein, D]] |
| - | [[Category: Ji, Q | + | [[Category: Ji, Q]] |
| - | [[Category: Jin, M | + | [[Category: Jin, M]] |
| - | [[Category: Kadalbajoo, M | + | [[Category: Kadalbajoo, M]] |
| - | [[Category: Kleinberg, A | + | [[Category: Kleinberg, A]] |
| - | [[Category: Mulvihill, M J | + | [[Category: Mulvihill, M J]] |
| - | [[Category: Pachter, J | + | [[Category: Pachter, J]] |
| - | [[Category: Siu, K | + | [[Category: Siu, K]] |
| - | [[Category: Thelemann, A | + | [[Category: Thelemann, A]] |
| - | [[Category: Wang, J | + | [[Category: Wang, J]] |
| - | [[Category: Yao, Y | + | [[Category: Yao, Y]] |
[[Category: Kinase]] | [[Category: Kinase]] | ||
[[Category: Transferase-transferase inhibitor complex]] | [[Category: Transferase-transferase inhibitor complex]] | ||
Revision as of 04:37, 25 December 2014
ACK1 kinase in complex with the inhibitor cis-3-[8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl]cyclobutanol
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Categories: Homo sapiens | Bhagwat, S | Bittner, M | Cooke, A | Crew, A P | Epstein, D | Ji, Q | Jin, M | Kadalbajoo, M | Kleinberg, A | Mulvihill, M J | Pachter, J | Siu, K | Thelemann, A | Wang, J | Yao, Y | Kinase | Transferase-transferase inhibitor complex
