|
|
| Line 3: |
Line 3: |
| | <StructureSection load='5l4q' size='340' side='right'caption='[[5l4q]], [[Resolution|resolution]] 1.97Å' scene=''> | | <StructureSection load='5l4q' size='340' side='right'caption='[[5l4q]], [[Resolution|resolution]] 1.97Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5l4q]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5L4Q OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5L4Q FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5l4q]] 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=5L4Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5L4Q 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=LKB:~{N}-[5-(4-CYANOPHENYL)-1~{H}-PYRROLO[2,3-B]PYRIDIN-3-YL]PYRIDINE-3-CARBOXAMIDE'>LKB</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]] 1.97Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AAK1, KIAA1048 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=LKB:~{N}-[5-(4-CYANOPHENYL)-1~{H}-PYRROLO[2,3-B]PYRIDIN-3-YL]PYRIDINE-3-CARBOXAMIDE'>LKB</scene></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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5l4q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l4q OCA], [https://pdbe.org/5l4q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5l4q RCSB], [https://www.ebi.ac.uk/pdbsum/5l4q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5l4q ProSAT]</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=5l4q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l4q OCA], [http://pdbe.org/5l4q PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5l4q RCSB], [http://www.ebi.ac.uk/pdbsum/5l4q PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5l4q 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 == |
| Line 24: |
Line 23: |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Non-specific serine/threonine protein kinase]] | + | [[Category: Abdul Azeez KR]] |
| - | [[Category: Azeez, K R.Abdul]]
| + | [[Category: Bountra C]] |
| - | [[Category: Bountra, C]] | + | [[Category: Edwards AM]] |
| - | [[Category: Delft, F von]]
| + | [[Category: Elkins JM]] |
| - | [[Category: Edwards, A M]] | + | [[Category: Fox N]] |
| - | [[Category: Elkins, J M]] | + | [[Category: Gileadi O]] |
| - | [[Category: Fox, N]] | + | [[Category: Knapp S]] |
| - | [[Category: Gileadi, O]] | + | [[Category: Sorrell FJ]] |
| - | [[Category: Knapp, S]] | + | [[Category: Williams E]] |
| - | [[Category: Sorrell, F J]] | + | [[Category: Von Delft F]] |
| - | [[Category: Williams, E]] | + | |
| - | [[Category: Kinase kinase domain]] | + | |
| - | [[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
There are currently no approved drugs for the treatment of emerging viral infections, such as dengue and Ebola. Adaptor-associated kinase 1 (AAK1) is a cellular serine-threonine protein kinase that functions as a key regulator of the clathrin-associated host adaptor proteins and regulates the intracellular trafficking of multiple unrelated RNA viruses. Moreover, AAK1 is overexpressed specifically in dengue virus-infected but not bystander cells. Because AAK1 is a promising antiviral drug target, we have embarked on an optimization campaign of a previously identified 7-azaindole analogue, yielding novel pyrrolo[2,3- b]pyridines with high AAK1 affinity. The optimized compounds demonstrate improved activity against dengue virus both in vitro and in human primary dendritic cells and the unrelated Ebola virus. These findings demonstrate that targeting cellular AAK1 may represent a promising broad-spectrum antiviral strategy.
Synthesis and Structure-Activity Relationships of 3,5-Disubstituted-pyrrolo[2,3- b]pyridines as Inhibitors of Adaptor-Associated Kinase 1 with Antiviral Activity.,Verdonck S, Pu SY, Sorrell FJ, Elkins JM, Froeyen M, Gao LJ, Prugar LI, Dorosky DE, Brannan JM, Barouch-Bentov R, Knapp S, Dye JM, Herdewijn P, Einav S, De Jonghe S J Med Chem. 2019 Jun 27;62(12):5810-5831. doi: 10.1021/acs.jmedchem.9b00136. Epub, 2019 Jun 12. PMID:31136173[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
- ↑ Verdonck S, Pu SY, Sorrell FJ, Elkins JM, Froeyen M, Gao LJ, Prugar LI, Dorosky DE, Brannan JM, Barouch-Bentov R, Knapp S, Dye JM, Herdewijn P, Einav S, De Jonghe S. Synthesis and Structure-Activity Relationships of 3,5-Disubstituted-pyrrolo[2,3- b]pyridines as Inhibitors of Adaptor-Associated Kinase 1 with Antiviral Activity. J Med Chem. 2019 Jun 27;62(12):5810-5831. doi: 10.1021/acs.jmedchem.9b00136. Epub, 2019 Jun 12. PMID:31136173 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b00136
|
