5l4q
From Proteopedia
(Difference between revisions)
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==Crystal Structure of Adaptor Protein 2 Associated Kinase 1 (AAK1) in Complex with LKB1 (AAK1 Dual Inhibitor)== | ==Crystal Structure of Adaptor Protein 2 Associated Kinase 1 (AAK1) in Complex with LKB1 (AAK1 Dual Inhibitor)== | ||
| - | <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. 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 [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> |
</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='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> | ||
| + | <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='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='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'>[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]</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> | [[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> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == 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<ref>PMID:31136173</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 5l4q" style="background-color:#fffaf0;"></div> | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human]] | ||
| + | [[Category: Large Structures]] | ||
[[Category: Non-specific serine/threonine protein kinase]] | [[Category: Non-specific serine/threonine protein kinase]] | ||
[[Category: Azeez, K R.Abdul]] | [[Category: Azeez, K R.Abdul]] | ||
Revision as of 06:25, 3 July 2019
Crystal Structure of Adaptor Protein 2 Associated Kinase 1 (AAK1) in Complex with LKB1 (AAK1 Dual Inhibitor)
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