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| | <StructureSection load='3qs9' size='340' side='right'caption='[[3qs9]], [[Resolution|resolution]] 7.80Å' scene=''> | | <StructureSection load='3qs9' size='340' side='right'caption='[[3qs9]], [[Resolution|resolution]] 7.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3qs9]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QS9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QS9 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3qs9]] is a 8 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=3QS9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3QS9 FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3qs7|3qs7]]</div></td></tr> | + | </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=3qs9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qs9 OCA], [https://pdbe.org/3qs9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qs9 RCSB], [https://www.ebi.ac.uk/pdbsum/3qs9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qs9 ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FLT3LG ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), FLT3, STK1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=3qs9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qs9 OCA], [https://pdbe.org/3qs9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3qs9 RCSB], [https://www.ebi.ac.uk/pdbsum/3qs9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3qs9 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| - | == Disease == | |
| - | [[https://www.uniprot.org/uniprot/FLT3_HUMAN FLT3_HUMAN]] Defects in FLT3 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 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 == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/FLT3L_HUMAN FLT3L_HUMAN]] Stimulates the proliferation of early hematopoietic cells by activating FLT3. Synergizes well with a number of other colony stimulating factors and interleukins. [[https://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>
| + | [https://www.uniprot.org/uniprot/FLT3L_HUMAN FLT3L_HUMAN] Stimulates the proliferation of early hematopoietic cells by activating FLT3. Synergizes well with a number of other colony stimulating factors and interleukins. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Receptor protein-tyrosine kinase]]
| + | [[Category: Savvides SN]] |
| - | [[Category: Savvides, S N]] | + | [[Category: Verstraete K]] |
| - | [[Category: Verstraete, K]] | + | |
| - | [[Category: Cell surface]]
| + | |
| - | [[Category: Cytokine-signaling protein complex]]
| + | |
| - | [[Category: Extracellular complex]]
| + | |
| - | [[Category: Four-helical bundle cytokine]]
| + | |
| - | [[Category: Hematopoietic cytokine-receptor complex]]
| + | |
| - | [[Category: Immunoglobulin-like domain]]
| + | |
| - | [[Category: Receptor tyrosine kinase]]
| + | |
| Structural highlights
Function
FLT3L_HUMAN Stimulates the proliferation of early hematopoietic cells by activating FLT3. Synergizes well with a number of other colony stimulating factors and interleukins.
Publication Abstract from PubMed
The class-III receptor tyrosine kinase (RTKIII) Flt3 and its cytokine ligand (FL) play central roles in hematopoiesis and the immune system, by establishing signaling cascades crucial for the development and homeostasis of hematopoietic progenitors and antigen-presenting dendritic cells. However, Flt3 is also one of the most frequently mutated receptors in hematological malignancies and is currently a major prognostic factor and clinical target for acute myeloid leukemia (AML). Here, we report the structural basis for the Flt3 ligand-receptor complex and unveil an unanticipated extracellular assembly unlike any other RTKIII/V complex characterized to date. FL induces dimerization of Flt3 via a remarkably compact binding epitope localized at the tip of extracellular domain 3 of Flt3, and invokes a ternary complex devoid of homotypic receptor interactions. Comparisons of Flt3 with homologous receptors and available mutagenesis data for FL have allowed us to rationalize the unique features of the Flt3 extracellular assembly. Furthermore, thermodynamic dissection of complex formation points to a pronounced enthalpically-driven binding event coupled to an entropic penalty. Together, our data suggest that the high-affinity Flt3-FL complex is driven in part by a single preformed binding epitope on FL reminiscent of a 'lock-and-key' binding mode, thereby setting the stage for antagonist design.
Structural insights into the extracellular assembly of the hematopoietic Flt3 signaling complex.,Verstraete K, Vandriessche G, Januar M, Elegheert J, Shkumatov AV, Desfosses A, Van Craenenbroeck K, Svergun DI, Gutsche I, Vergauwen B, Savvides SN Blood. 2011 Mar 9. PMID:21389326[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Verstraete K, Vandriessche G, Januar M, Elegheert J, Shkumatov AV, Desfosses A, Van Craenenbroeck K, Svergun DI, Gutsche I, Vergauwen B, Savvides SN. Structural insights into the extracellular assembly of the hematopoietic Flt3 signaling complex. Blood. 2011 Mar 9. PMID:21389326 doi:10.1182/blood-2011-01-329532
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