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New page: ==Crystal Structure of Adaptor Protein 2 Associated Kinase (AAK1) in complex with small molecule inhibitor== <StructureSection load='4wsq' size='340' side='right' caption='4wsq, [[Reso... |
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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 [ | <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><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='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'>[ | <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 == | |||
[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;"> | |||
== 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<ref>PMID:26853940</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4wsq" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Abdul K]] | ||
[[Category: | [[Category: Arrowsmith CH]] | ||
[[Category: | [[Category: Bountra C]] | ||
[[Category: Edwards | [[Category: Edwards AM]] | ||
[[Category: Elkins | [[Category: Elkins JM]] | ||
[[Category: Gileadi | [[Category: Gileadi O]] | ||
[[Category: Knapp | [[Category: Knapp S]] | ||
[[Category: Krojer | [[Category: Krojer T]] | ||
[[Category: Sorrell FJ]] | |||
[[Category: Sorrell | [[Category: Williams E]] | ||
[[Category: Williams | [[Category: Von Delft F]] | ||
[[Category: | |||
Latest revision as of 13:44, 10 January 2024
Crystal Structure of Adaptor Protein 2 Associated Kinase (AAK1) in complex with small molecule inhibitorCrystal Structure of Adaptor Protein 2 Associated Kinase (AAK1) in complex with small molecule inhibitor
Structural highlights
FunctionAAK1_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 PubMedThe 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
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