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''' | ==Crystal structure of the FLT3 kinase domain bound to the inhibitor quizartinib (AC220)== | ||
<StructureSection load='4xuf' size='340' side='right' caption='[[4xuf]], [[Resolution|resolution]] 3.20Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4xuf]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XUF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XUF FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=P30:1-(5-TERT-BUTYL-1,2-OXAZOL-3-YL)-3-(4-{7-[2-(MORPHOLIN-4-YL)ETHOXY]IMIDAZO[2,1-B][1,3]BENZOTHIAZOL-2-YL}PHENYL)UREA'>P30</scene></td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </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=4xuf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xuf OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4xuf RCSB], [http://www.ebi.ac.uk/pdbsum/4xuf PDBsum]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[[http://www.uniprot.org/uniprot/FLT3_HUMAN FLT3_HUMAN]] Defects in FLT3 are a cause of acute myelogenous leukemia (AML) [MIM:[http://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 FLT3 are frequent 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 activation loop of the kinase domain can result in a constitutively activated kinase.<ref>PMID:11090077</ref> <ref>PMID:16266983</ref> <ref>PMID:14504097</ref> <ref>PMID:9737679</ref> <ref>PMID:18305215</ref> <ref>PMID:11290608</ref> <ref>PMID:8946930</ref> <ref>PMID:11442493</ref> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/FLT3_HUMAN FLT3_HUMAN]] Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells. Promotes phosphorylation of SHC1 and AKT1, and activation of the downstream effector MTOR. Promotes activation of RAS signaling and phosphorylation of downstream kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation of FES, FER, PTPN6/SHP, PTPN11/SHP-2, PLCG1, and STAT5A and/or STAT5B. Activation of wild-type FLT3 causes only marginal activation of STAT5A or STAT5B. Mutations that cause constitutive kinase activity promote cell proliferation and resistance to apoptosis via the activation of multiple signaling pathways.<ref>PMID:7507245</ref> <ref>PMID:10080542</ref> <ref>PMID:11090077</ref> <ref>PMID:16266983</ref> <ref>PMID:16627759</ref> <ref>PMID:18490735</ref> <ref>PMID:20111072</ref> <ref>PMID:21067588</ref> <ref>PMID:21262971</ref> <ref>PMID:21516120</ref> <ref>PMID:14504097</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
More than 30% of acute myeloid leukemia (AML) patients possess activating mutations in the receptor tyrosine kinase FMS-like tyrosine kinase 3 or FLT3. A small-molecule inhibitor of FLT3 (known as quizartinib or AC220) that is currently in clinical trials appears promising for the treatment of AML. Here, we report the co-crystal structure of the kinase domain of FLT3 in complex with quizartinib. FLT3 with quizartinib bound adopts an "Abl-like" inactive conformation with the activation loop stabilized in the "DFG-out" orientation and folded back onto the kinase domain. This conformation is similar to that observed for the uncomplexed intracellular domain of FLT3 as well as for related receptor tyrosine kinases, except for a localized induced fit in the activation loop. The co-crystal structure reveals the interactions between quizartinib and the active site of FLT3 that are key for achieving its high potency against both wild-type FLT3 as well as a FLT3 variant observed in many AML patients. This co-complex further provides a structural rationale for quizartinib-resistance mutations. | |||
Crystal Structure of the FLT3 Kinase Domain Bound to the Inhibitor Quizartinib (AC220).,Zorn JA, Wang Q, Fujimura E, Barros T, Kuriyan J PLoS One. 2015 Apr 2;10(4):e0121177. doi: 10.1371/journal.pone.0121177., eCollection 2015. PMID:25837374<ref>PMID:25837374</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
[[Category: | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Receptor protein-tyrosine kinase]] | |||
[[Category: Barros, T]] | |||
[[Category: Fujimura, E]] | |||
[[Category: Kuriyan, J]] | [[Category: Kuriyan, J]] | ||
[[Category: Wang, Q]] | [[Category: Wang, Q]] | ||
[[Category: Zorn, J | [[Category: Zorn, J A]] | ||
[[Category: Ac220]] | |||
[[Category: Flt3]] | |||
[[Category: Quizartinib]] | |||
[[Category: Receptor tyrosine kinase]] | |||
[[Category: Transferase-transferase inhibitor complex]] | |||