5iug
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | The entry | + | ==Crystal Structure of Anaplastic Lymphoma Kinase (ALK) in complex with 5a== |
| + | <StructureSection load='5iug' size='340' side='right' caption='[[5iug]], [[Resolution|resolution]] 1.93Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5iug]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IUG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5IUG FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=729:N-[3-(4-{[(5-TERT-BUTYL-1,2-OXAZOL-3-YL)CARBAMOYL]AMINO}-3-METHYLPHENYL)-1H-PYRAZOL-5-YL]-4-[(4-METHYLPIPERAZIN-1-YL)METHYL]BENZAMIDE'>729</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5iuh|5iuh]], [[5iui|5iui]]</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=5iug FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5iug OCA], [http://pdbe.org/5iug PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5iug RCSB], [http://www.ebi.ac.uk/pdbsum/5iug PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [[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. | ||
| + | == Function == | ||
| + | [[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> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Most anaplastic lymphoma kinase (ALK) inhibitors adopt a type I binding mode, but only limited type II ALK structural studies are available. Herein, we present the structure of ALK in complex with N1-(3-4-[([5-(tert-butyl)-3-isoxazolyl]aminocarbonyl)amino]-3-methylphenyl-1H-5-p yrazolyl)-4-[(4-methylpiperazino)methyl]benzamide (5a), a novel ALK inhibitor adopting a type II binding mode. It revealed binding of 5a resulted in the conformational change and reposition of the activation loop, alphaC-helix, and juxtamembrane domain, which are all important domains for the autoinhibition mechanism and downstream signal pathway regulation of ALK. A structure-activity relationship study revealed that modifications to the structure of 5a led to significant differences in the ALK potency and altered the protein structure of ALK. To the best of our knowledge, this is the first structural biology study to directly observe how changes in the structure of a small molecule can regulate the switch between the type I and type II binding modes and induce dramatic conformational changes. | ||
| - | + | Pyrazolylamine Derivatives Reveal the Conformational Switching between Type I and Type II Binding Modes of Anaplastic Lymphoma Kinase (ALK).,Tu CH, Lin WH, Peng YH, Hsu T, Wu JS, Chang CY, Lu CT, Lyu PC, Shih C, Jiaang WT, Wu SY J Med Chem. 2016 Apr 28;59(8):3906-19. doi: 10.1021/acs.jmedchem.6b00106. Epub, 2016 Apr 12. PMID:27031565<ref>PMID:27031565</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: Wu, S | + | <div class="pdbe-citations 5iug" style="background-color:#fffaf0;"></div> |
| - | [[Category: | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Receptor protein-tyrosine kinase]] | ||
| + | [[Category: Tu, C H]] | ||
| + | [[Category: Wu, S Y]] | ||
| + | [[Category: Catalytic domain]] | ||
| + | [[Category: Transferase]] | ||
Revision as of 15:55, 1 June 2016
Crystal Structure of Anaplastic Lymphoma Kinase (ALK) in complex with 5a
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