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| | ==Crystal Structure of Adaptor Protein 2 Associated Kinase (AAK1) in complex with small molecule inhibitor== | | ==Crystal Structure of Adaptor Protein 2 Associated Kinase (AAK1) in complex with small molecule inhibitor== |
| - | <StructureSection load='4wsq' size='340' side='right' caption='[[4wsq]], [[Resolution|resolution]] 1.95Å' scene=''> | + | <StructureSection load='4wsq' size='340' side='right'caption='[[4wsq]], [[Resolution|resolution]] 1.95Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4wsq]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WSQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4WSQ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4wsq]] is a 2 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=4WSQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4WSQ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=KSA:K-252A'>KSA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.95Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=KSA:K-252A'>KSA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=4wsq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wsq OCA], [http://pdbe.org/4wsq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4wsq RCSB], [http://www.ebi.ac.uk/pdbsum/4wsq PDBsum]</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=4wsq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wsq OCA], [https://pdbe.org/4wsq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4wsq RCSB], [https://www.ebi.ac.uk/pdbsum/4wsq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4wsq ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/AAK1_HUMAN AAK1_HUMAN]] Regulates clathrin-mediated endocytosis by phosphorylating the AP2M1/mu2 subunit of the adaptor protein complex 2 (AP-2) which ensures high affinity binding of AP-2 to cargo membrane proteins during the initial stages of endocytosis. Isoform 1 and isoform 2 display similar levels of kinase activity towards AP2M1. Regulates phosphorylation of other AP-2 subunits as well as AP-2 localization and AP-2-mediated internalization of ligand complexes. Phosphorylates NUMB and regulates its cellular localization, promoting NUMB localization to endosomes. Binds to and stabilizes the activated form of NOTCH1, increases its localization in endosomes and regulates its transcriptional activity.<ref>PMID:12952931</ref> <ref>PMID:17494869</ref> <ref>PMID:18657069</ref> <ref>PMID:21464124</ref> | + | [https://www.uniprot.org/uniprot/AAK1_HUMAN AAK1_HUMAN] Regulates clathrin-mediated endocytosis by phosphorylating the AP2M1/mu2 subunit of the adaptor protein complex 2 (AP-2) which ensures high affinity binding of AP-2 to cargo membrane proteins during the initial stages of endocytosis. Isoform 1 and isoform 2 display similar levels of kinase activity towards AP2M1. Regulates phosphorylation of other AP-2 subunits as well as AP-2 localization and AP-2-mediated internalization of ligand complexes. Phosphorylates NUMB and regulates its cellular localization, promoting NUMB localization to endosomes. Binds to and stabilizes the activated form of NOTCH1, increases its localization in endosomes and regulates its transcriptional activity.<ref>PMID:12952931</ref> <ref>PMID:17494869</ref> <ref>PMID:18657069</ref> <ref>PMID:21464124</ref> |
| | <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: Non-specific serine/threonine protein kinase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Abdul, K]] | + | [[Category: Large Structures]] |
| - | [[Category: Arrowsmith, C H]] | + | [[Category: Abdul K]] |
| - | [[Category: Bountra, C]] | + | [[Category: Arrowsmith CH]] |
| - | [[Category: Delft, F Von]] | + | [[Category: Bountra C]] |
| - | [[Category: Edwards, A M]] | + | [[Category: Edwards AM]] |
| - | [[Category: Elkins, J M]] | + | [[Category: Elkins JM]] |
| - | [[Category: Gileadi, O]] | + | [[Category: Gileadi O]] |
| - | [[Category: Knapp, S]] | + | [[Category: Knapp S]] |
| - | [[Category: Krojer, T]] | + | [[Category: Krojer T]] |
| - | [[Category: Structural genomic]]
| + | [[Category: Sorrell FJ]] |
| - | [[Category: Sorrell, F J]] | + | [[Category: Williams E]] |
| - | [[Category: Williams, E]] | + | [[Category: Von Delft F]] |
| - | [[Category: Catalytic domain]] | + | |
| - | [[Category: Kinase]]
| + | |
| - | [[Category: Protein binding]]
| + | |
| - | [[Category: Protein kinase]]
| + | |
| - | [[Category: Protein kinase inhibitor]]
| + | |
| - | [[Category: Small-molecule]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
AAK1_HUMAN Regulates clathrin-mediated endocytosis by phosphorylating the AP2M1/mu2 subunit of the adaptor protein complex 2 (AP-2) which ensures high affinity binding of AP-2 to cargo membrane proteins during the initial stages of endocytosis. Isoform 1 and isoform 2 display similar levels of kinase activity towards AP2M1. Regulates phosphorylation of other AP-2 subunits as well as AP-2 localization and AP-2-mediated internalization of ligand complexes. Phosphorylates NUMB and regulates its cellular localization, promoting NUMB localization to endosomes. Binds to and stabilizes the activated form of NOTCH1, increases its localization in endosomes and regulates its transcriptional activity.[1] [2] [3] [4]
Publication Abstract from PubMed
The highly diverse Numb-associated kinase (NAK) family has been linked to broad cellular functions including receptor-mediated endocytosis, Notch pathway modulation, osteoblast differentiation, and dendrite morphogenesis. Consequently, NAK kinases play a key role in a diverse range of diseases from Parkinson's and prostate cancer to HIV. Due to the plasticity of this kinase family, NAK kinases are often inhibited by approved or investigational drugs and have been associated with side effects, but they are also potential drug targets. The presence of cysteine residues in some NAK family members provides the possibility for selective targeting via covalent inhibition. Here we report the first high-resolution structures of kinases AAK1 and BIKE in complex with two drug candidates. The presented data allow a comprehensive structural characterization of the NAK kinase family and provide the basis for rational design of selective NAK inhibitors.
Family-wide Structural Analysis of Human Numb-Associated Protein Kinases.,Sorrell FJ, Szklarz M, Abdul Azeez KR, Elkins JM, Knapp S Structure. 2016 Jan 29. pii: S0969-2126(16)00008-3. doi:, 10.1016/j.str.2015.12.015. PMID:26853940[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Conner SD, Schmid SL. Differential requirements for AP-2 in clathrin-mediated endocytosis. J Cell Biol. 2003 Sep 1;162(5):773-9. PMID:12952931 doi:http://dx.doi.org/10.1083/jcb.200304069
- ↑ Henderson DM, Conner SD. A novel AAK1 splice variant functions at multiple steps of the endocytic pathway. Mol Biol Cell. 2007 Jul;18(7):2698-706. Epub 2007 May 9. PMID:17494869 doi:http://dx.doi.org/10.1091/mbc.E06-09-0831
- ↑ Sorensen EB, Conner SD. AAK1 regulates Numb function at an early step in clathrin-mediated endocytosis. Traffic. 2008 Sep;9(10):1791-800. doi: 10.1111/j.1600-0854.2008.00790.x. Epub, 2008 Jul 24. PMID:18657069 doi:http://dx.doi.org/10.1111/j.1600-0854.2008.00790.x
- ↑ Gupta-Rossi N, Ortica S, Meas-Yedid V, Heuss S, Moretti J, Olivo-Marin JC, Israel A. The adaptor-associated kinase 1, AAK1, is a positive regulator of the Notch pathway. J Biol Chem. 2011 May 27;286(21):18720-30. doi: 10.1074/jbc.M110.190769. Epub, 2011 Apr 4. PMID:21464124 doi:http://dx.doi.org/10.1074/jbc.M110.190769
- ↑ Sorrell FJ, Szklarz M, Abdul Azeez KR, Elkins JM, Knapp S. Family-wide Structural Analysis of Human Numb-Associated Protein Kinases. Structure. 2016 Jan 29. pii: S0969-2126(16)00008-3. doi:, 10.1016/j.str.2015.12.015. PMID:26853940 doi:http://dx.doi.org/10.1016/j.str.2015.12.015
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