View source for 4hvs


==Crystal structure of KIT kinase domain with a small molecule inhibitor, PLX647==
<StructureSection load='4hvs' size='340' side='right'caption='[[4hvs]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4hvs]] 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=4HVS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HVS 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]] 1.9&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=647:5-(1H-PYRROLO[2,3-B]PYRIDIN-3-YLMETHYL)-N-[4-(TRIFLUOROMETHYL)BENZYL]PYRIDIN-2-AMINE'>647</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=4hvs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hvs OCA], [https://pdbe.org/4hvs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hvs RCSB], [https://www.ebi.ac.uk/pdbsum/4hvs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hvs 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 ==
Inflammation and cancer, two therapeutic areas historically addressed by separate drug discovery efforts, are now coupled in treatment approaches by a growing understanding of the dynamic molecular dialogues between immune and cancer cells. Agents that target specific compartments of the immune system, therefore, not only bring new disease modifying modalities to inflammatory diseases, but also offer a new avenue to cancer therapy by disrupting immune components of the microenvironment that foster tumor growth, progression, immune evasion, and treatment resistance. McDonough feline sarcoma viral (v-fms) oncogene homolog (FMS) and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) are two hematopoietic cell surface receptors that regulate the development and function of macrophages and mast cells, respectively. We disclose a highly specific dual FMS and KIT kinase inhibitor developed from a multifaceted chemical scaffold. As expected, this inhibitor blocks the activation of macrophages, osteoclasts, and mast cells controlled by these two receptors. More importantly, the dual FMS and KIT inhibition profile has translated into a combination of benefits in preclinical disease models of inflammation and cancer.

Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor.,Zhang C, Ibrahim PN, Zhang J, Burton EA, Habets G, Zhang Y, Powell B, West BL, Matusow B, Tsang G, Shellooe R, Carias H, Nguyen H, Marimuthu A, Zhang KY, Oh A, Bremer R, Hurt CR, Artis DR, Wu G, Nespi M, Spevak W, Lin P, Nolop K, Hirth P, Tesch GH, Bollag G Proc Natl Acad Sci U S A. 2013 Mar 14. PMID:23493555<ref>PMID:23493555</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4hvs" 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: Zhang C]]
[[Category: Zhang Y]]