View source for 6kla


==Crystal structure of human c-KIT kinase domain in complex with compound 15a==
<StructureSection load='6kla' size='340' side='right'caption='[[6kla]], [[Resolution|resolution]] 2.11&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6kla]] 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=6KLA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6KLA FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.109&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DJX:N-[6-(4-ethylpiperazin-1-yl)-2-methyl-pyrimidin-4-yl]-5-pyridin-4-yl-1,3-thiazol-2-amine'>DJX</scene></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=6kla FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6kla OCA], [https://pdbe.org/6kla PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6kla RCSB], [https://www.ebi.ac.uk/pdbsum/6kla PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6kla ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/KIT_HUMAN KIT_HUMAN] Defects in KIT are a cause of piebald trait (PBT) [MIM:[https://omim.org/entry/172800 172800]; also known as piebaldism. PBT is an autosomal dominant genetic developmental abnormality of pigmentation characterized by congenital patches of white skin and hair that lack melanocytes.<ref>PMID:1376329</ref> <ref>PMID:1370874</ref> <ref>PMID:1717985</ref> <ref>PMID:7687267</ref> <ref>PMID:8680409</ref> <ref>PMID:9029028</ref> <ref>PMID:9450866</ref> <ref>PMID:9699740</ref> <ref>PMID:11074500</ref>   Defects in KIT are a cause of gastrointestinal stromal tumor (GIST) [MIM:[https://omim.org/entry/606764 606764].<ref>PMID:9029028</ref> <ref>PMID:9697690</ref> <ref>PMID:9438854</ref> <ref>PMID:11505412</ref> <ref>PMID:15824741</ref>   Defects in KIT have been associated with testicular germ cell tumor (TGCT) [MIM:[https://omim.org/entry/273300 273300]. A common solid malignancy in males. Germ cell tumors of the testis constitute 95% of all testicular neoplasms.<ref>PMID:9029028</ref>   Defects in KIT are a cause of acute myelogenous leukemia (AML) [MIM:[https://omim.org/entry/601626 601626]. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development. Note=Somatic mutations that lead to constitutive activation of KIT are detected in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the kinase domain can result in a constitutively activated kinase.<ref>PMID:9029028</ref> 
== Function ==
[https://www.uniprot.org/uniprot/KIT_HUMAN KIT_HUMAN] Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways. Phosphorylates PIK3R1, PLCG1, SH2B2/APS and CBL. Activates the AKT1 signaling pathway by phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Activated KIT also transmits signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3, STAT5A and STAT5B. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KIT signaling is modulated by protein phosphatases, and by rapid internalization and degradation of the receptor. Activated KIT promotes phosphorylation of the protein phosphatases PTPN6/SHP-1 and PTPRU, and of the transcription factors STAT1, STAT3, STAT5A and STAT5B. Promotes phosphorylation of PIK3R1, CBL, CRK (isoform Crk-II), LYN, MAPK1/ERK2 and/or MAPK3/ERK1, PLCG1, SRC and SHC1.<ref>PMID:7520444</ref> <ref>PMID:9528781</ref> <ref>PMID:10397721</ref> <ref>PMID:12444928</ref> <ref>PMID:12878163</ref> <ref>PMID:12511554</ref> <ref>PMID:17904548</ref> <ref>PMID:19265199</ref> <ref>PMID:21640708</ref> <ref>PMID:21135090</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Gastrointestinal stromal tumors (GISTs) are prototypes of stem cell factor receptor (c-KIT)-driven cancer. Two receptor tyrosine kinases, c-KIT and fms-tyrosine kinase (FLT3), are frequently mutated in AML patients, and these mutations are associated with poor prognosis. In this study, we discovered a multitargeted tyrosine kinase inhibitor, compound 15a, with potent inhibition against single or double mutations of c-KIT developed in GISTs. Moreover, crystal structure analysis revealed the unique binding mode of 15a with c-KIT and may elucidate its high potency in inhibiting c-KIT kinase activity. Compound 15a inhibited cell proliferation and induced apoptosis by targeting c-KIT in c-KIT-mutant GIST cell lines. The antitumor effects of 15a were also demonstrated in GIST430 and GIST patient-derived xenograft (PDX) models. Further studies demonstrated that 15a inhibited the proliferation of c-KIT- and FLT3-driven AML cells in vitro and in vivo. The results of this study suggest that 15a may be a potential anticancer drug for the treatment of GISTs and AML.

Identification of a Multitargeted Tyrosine Kinase Inhibitor for the Treatment of Gastrointestinal Stromal Tumors (GISTs) and Acute Myeloid Leukemia (AML).,Lin WH, Wu S, Yeh TK, Chen CT, Song JS, Shiao HY, Kuo CC, Hsu T, Lu CT, Wang PC, Wu TS, Peng YH, Lin HY, Chen CP, Weng YL, Kung FC, Wu MH, Su YC, Huang KW, Chou LH, Hsueh CC, Yen KJ, Kuo PC, Huang CL, Chen LT, Shih C, Tsai HJ, Jiaang WT J Med Chem. 2019 Nov 13. doi: 10.1021/acs.jmedchem.9b01229. PMID:31721578<ref>PMID:31721578</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6kla" style="background-color:#fffaf0;"></div>

==See Also==
*[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Hsueh CC]]
[[Category: Peng YH]]
[[Category: Wu SY]]
[[Category: Wu TS]]