4fnw

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{{STRUCTURE_4fnw| PDB=4fnw | SCENE= }}
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==Crystal structure of the apo F1174L anaplastic lymphoma kinase catalytic domain==
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===Crystal structure of the apo F1174L anaplastic lymphoma kinase catalytic domain===
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<StructureSection load='4fnw' size='340' side='right' caption='[[4fnw]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
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{{ABSTRACT_PUBMED_22932897}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4fnw]] 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=4FNW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4FNW FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4fnx|4fnx]], [[4fny|4fny]], [[4fnz|4fnz]], [[4fob|4fob]], [[4foc|4foc]], [[4fod|4fod]]</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ALK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
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<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>
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<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=4fnw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fnw OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4fnw RCSB], [http://www.ebi.ac.uk/pdbsum/4fnw PDBsum]</span></td></tr>
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</table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/ALK_HUMAN ALK_HUMAN]] Note=A chromosomal aberration involving ALK is found in a form of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with NPM1. The resulting chimeric NPM1-ALK protein homodimerize and the kinase becomes constitutively activated. The constitutively active fusion proteins are responsible for 5-10% of non-Hodgkin lymphomas. Note=A chromosomal aberration involving ALK is associated with inflammatory myofibroblastic tumors (IMTs). Translocation t(2;11)(p23;p15) with CARS; translocation t(2;4)(p23;q21) with SEC31A. Note=A chromosomal aberration involving ALK is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALO17. Defects in ALK are the cause of susceptibility to neuroblastoma type 3 (NBLST3) [MIM:[http://omim.org/entry/613014 613014]]. Neuroblastoma is a common neoplasm of early childhood arising from embryonic cells that form the primitive neural crest and give rise to the adrenal medulla and the sympathetic nervous system.<ref>PMID:18724359</ref> <ref>PMID:18923523</ref> <ref>PMID:18923525</ref> Note=The ALK signaling pathway plays an important role in glioblastoma, the most common malignant brain tumor of adults and one of the most lethal cancers. It regulates both glioblastoma migration and growth.
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== Function ==
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[[http://www.uniprot.org/uniprot/ALK_HUMAN ALK_HUMAN]] Neuronal orphan receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system. Transduces signals from ligands at the cell surface, through specific activation of the mitogen-activated protein kinase (MAPK) pathway. Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif. Following activation by ligand, ALK induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Acts as a receptor for ligands pleiotrophin (PTN), a secreted growth factor, and midkine (MDK), a PTN-related factor, thus participating in PTN and MDK signal transduction. PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation. MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction. Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase. Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK.<ref>PMID:11387242</ref> <ref>PMID:11121404</ref> <ref>PMID:11278720</ref> <ref>PMID:11809760</ref> <ref>PMID:12107166</ref> <ref>PMID:12122009</ref> <ref>PMID:15226403</ref> <ref>PMID:15908427</ref> <ref>PMID:16317043</ref> <ref>PMID:17274988</ref> <ref>PMID:16878150</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that, when genetically altered by mutation, amplification, chromosomal translocation or inversion, has been shown to play an oncogenic role in certain cancers. Small molecule inhibitors targeting the kinase activity of ALK have proven to be effective therapies in certain ALK-driven malignancies and one such inhibitor, crizotinib, is now approved for the treatment of EML4-ALK-driven, non-small cell lung cancer. In neuroblastoma, activating point mutations in the ALK kinase domain can drive disease progression, with the two most common mutations being F1174L and R1275Q. We report here crystal structures of the ALK kinase domain containing the F1174L and R1275Q mutations. Also included are crystal structures of ALK in complex with novel small molecule ALK inhibitors, including a classic type II inhibitor, that stabilize previously unobserved conformations of the ALK activation loop. Collectively, these structures illustrate a different series of activation loop conformations than has been observed in previous ALK crystal structures and provide insight into the activating nature of the R1275Q mutation. The novel active site topologies presented here may also aid the structure-based drug design of a new generation of ALK inhibitors.
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==Disease==
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The R1275Q Neuroblastoma Mutant and Certain ATP-competitive Inhibitors Stabilize Alternative Activation Loop Conformations of Anaplastic Lymphoma Kinase.,Epstein LF, Chen H, Emkey R, Whittington DA J Biol Chem. 2012 Oct 26;287(44):37447-57. doi: 10.1074/jbc.M112.391425. Epub, 2012 Aug 29. PMID:22932897<ref>PMID:22932897</ref>
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[[http://www.uniprot.org/uniprot/ALK_HUMAN ALK_HUMAN]] Note=A chromosomal aberration involving ALK is found in a form of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with NPM1. The resulting chimeric NPM1-ALK protein homodimerize and the kinase becomes constitutively activated. The constitutively active fusion proteins are responsible for 5-10% of non-Hodgkin lymphomas. Note=A chromosomal aberration involving ALK is associated with inflammatory myofibroblastic tumors (IMTs). Translocation t(2;11)(p23;p15) with CARS; translocation t(2;4)(p23;q21) with SEC31A. Note=A chromosomal aberration involving ALK is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALO17. Defects in ALK are the cause of susceptibility to neuroblastoma type 3 (NBLST3) [MIM:[http://omim.org/entry/613014 613014]]. Neuroblastoma is a common neoplasm of early childhood arising from embryonic cells that form the primitive neural crest and give rise to the adrenal medulla and the sympathetic nervous system.<ref>PMID:18724359</ref><ref>PMID:18923523</ref><ref>PMID:18923525</ref> Note=The ALK signaling pathway plays an important role in glioblastoma, the most common malignant brain tumor of adults and one of the most lethal cancers. It regulates both glioblastoma migration and growth.
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==Function==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[http://www.uniprot.org/uniprot/ALK_HUMAN ALK_HUMAN]] Neuronal orphan receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system. Transduces signals from ligands at the cell surface, through specific activation of the mitogen-activated protein kinase (MAPK) pathway. Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif. Following activation by ligand, ALK induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Acts as a receptor for ligands pleiotrophin (PTN), a secreted growth factor, and midkine (MDK), a PTN-related factor, thus participating in PTN and MDK signal transduction. PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation. MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction. Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase. Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK.<ref>PMID:11387242</ref><ref>PMID:11121404</ref><ref>PMID:11278720</ref><ref>PMID:11809760</ref><ref>PMID:12107166</ref><ref>PMID:12122009</ref><ref>PMID:15226403</ref><ref>PMID:15908427</ref><ref>PMID:16317043</ref><ref>PMID:17274988</ref><ref>PMID:16878150</ref>
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</div>
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==About this Structure==
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==See Also==
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[[4fnw]] 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=4FNW OCA].
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*[[Tyrosine kinase|Tyrosine kinase]]
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== References ==
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==Reference==
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<references/>
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<references group="xtra"/><references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Receptor protein-tyrosine kinase]]
[[Category: Receptor protein-tyrosine kinase]]
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[[Category: Chen, H.]]
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[[Category: Chen, H]]
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[[Category: Epstein, L F.]]
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[[Category: Epstein, L F]]
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[[Category: Whittington, D A.]]
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[[Category: Whittington, D A]]
[[Category: Cd246]]
[[Category: Cd246]]
[[Category: Crizotinib]]
[[Category: Crizotinib]]

Revision as of 08:47, 15 February 2015

Crystal structure of the apo F1174L anaplastic lymphoma kinase catalytic domain

4fnw, resolution 1.75Å

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