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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==
==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]] 3.00&Aring;' scene=''>
<StructureSection load='4id7' size='340' side='right' caption='[[4id7]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
== 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>
<table><tr><td colspan='2'>[[4id7]] 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=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>
</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='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 HUMAN])</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>
<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://pdbe.org/4id7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4id7 RCSB], [http://www.ebi.ac.uk/pdbsum/4id7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4id7 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
Line 17: Line 18:
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
</div>
<div class="pdbe-citations 4id7" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Human]]
[[Category: Bhagwat, S]]
[[Category: Bhagwat, S]]
[[Category: Bittner, M]]
[[Category: Bittner, M]]

Revision as of 20:55, 5 August 2016

ACK1 kinase in complex with the inhibitor cis-3-[8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl]cyclobutanolACK1 kinase in complex with the inhibitor cis-3-[8-amino-1-(4-phenoxyphenyl)imidazo[1,5-a]pyrazin-3-yl]cyclobutanol

Structural highlights

4id7 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
Gene:ACK1, TNK2 (HUMAN)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]

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[12]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Kato J, Kaziro Y, Satoh T. Activation of the guanine nucleotide exchange factor Dbl following ACK1-dependent tyrosine phosphorylation. Biochem Biophys Res Commun. 2000 Feb 5;268(1):141-7. PMID:10652228 doi:http://dx.doi.org/10.1006/bbrc.2000.2106
  2. ↑ Teo M, Tan L, Lim L, Manser E. The tyrosine kinase ACK1 associates with clathrin-coated vesicles through a binding motif shared by arrestin and other adaptors. J Biol Chem. 2001 May 25;276(21):18392-8. Epub 2001 Feb 27. PMID:11278436 doi:http://dx.doi.org/10.1074/jbc.M008795200
  3. ↑ Yokoyama N, Lougheed J, Miller WT. Phosphorylation of WASP by the Cdc42-associated kinase ACK1: dual hydroxyamino acid specificity in a tyrosine kinase. J Biol Chem. 2005 Dec 23;280(51):42219-26. Epub 2005 Oct 28. PMID:16257963 doi:http://dx.doi.org/10.1074/jbc.M506996200
  4. ↑ van der Horst EH, Degenhardt YY, Strelow A, Slavin A, Chinn L, Orf J, Rong M, Li S, See LH, Nguyen KQ, Hoey T, Wesche H, Powers S. Metastatic properties and genomic amplification of the tyrosine kinase gene ACK1. Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15901-6. Epub 2005 Oct 24. PMID:16247015 doi:http://dx.doi.org/10.1073/pnas.0508014102
  5. ↑ Modzelewska K, Newman LP, Desai R, Keely PJ. Ack1 mediates Cdc42-dependent cell migration and signaling to p130Cas. J Biol Chem. 2006 Dec 8;281(49):37527-35. Epub 2006 Oct 12. PMID:17038317 doi:10.1074/jbc.M604342200
  6. ↑ Yokoyama N, Miller WT. Purification and enzyme activity of ACK1. Methods Enzymol. 2006;406:250-60. PMID:16472662 doi:http://dx.doi.org/10.1016/S0076-6879(06)06018-6
  7. ↑ Howlin J, Rosenkvist J, Andersson T. TNK2 preserves epidermal growth factor receptor expression on the cell surface and enhances migration and invasion of human breast cancer cells. Breast Cancer Res. 2008;10(2):R36. doi: 10.1186/bcr2087. Epub 2008 Apr 24. PMID:18435854 doi:http://dx.doi.org/10.1186/bcr2087
  8. ↑ Grovdal LM, Johannessen LE, Rodland MS, Madshus IH, Stang E. Dysregulation of Ack1 inhibits down-regulation of the EGF receptor. Exp Cell Res. 2008 Apr 1;314(6):1292-300. doi: 10.1016/j.yexcr.2007.12.017. Epub , 2008 Jan 5. PMID:18262180 doi:http://dx.doi.org/10.1016/j.yexcr.2007.12.017
  9. ↑ Pao-Chun L, Chan PM, Chan W, Manser E. Cytoplasmic ACK1 interaction with multiple receptor tyrosine kinases is mediated by Grb2: an analysis of ACK1 effects on Axl signaling. J Biol Chem. 2009 Dec 11;284(50):34954-63. doi: 10.1074/jbc.M109.072660. Epub, 2009 Oct 8. PMID:19815557 doi:10.1074/jbc.M109.072660
  10. ↑ Liu Y, Karaca M, Zhang Z, Gioeli D, Earp HS, Whang YE. Dasatinib inhibits site-specific tyrosine phosphorylation of androgen receptor by Ack1 and Src kinases. Oncogene. 2010 Jun 3;29(22):3208-16. doi: 10.1038/onc.2010.103. Epub 2010 Apr 12. PMID:20383201 doi:http://dx.doi.org/10.1038/onc.2010.103
  11. ↑ Mahajan K, Coppola D, Challa S, Fang B, Chen YA, Zhu W, Lopez AS, Koomen J, Engelman RW, Rivera C, Muraoka-Cook RS, Cheng JQ, Schonbrunn E, Sebti SM, Earp HS, Mahajan NP. Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation. PLoS One. 2010 Mar 19;5(3):e9646. doi: 10.1371/journal.pone.0009646. PMID:20333297 doi:10.1371/journal.pone.0009646
  12. ↑ 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. Discovery of potent, selective and orally bioavailable imidazo[1,5-a]pyrazine derived ACK1 inhibitors. 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 doi:http://dx.doi.org/10.1016/j.bmcl.2012.12.042

4id7, resolution 3.00Å

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