View source for 8gmc


==CRYSTAL STRUCTURE OF AP2 ASSOCIATED KINASE 1 COMPLEXED WITH 5-[(4-aminopiperidin-1-yl)methyl]-N-{3-[5-(propan-2-yl)-1,3,4-thiadiazol-2-yl]phenyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine==
<StructureSection load='8gmc' size='340' side='right'caption='[[8gmc]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8gmc]] 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=8GMC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8GMC FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=YFV:5-[(4-aminopiperidin-1-yl)methyl]-N-{3-[5-(propan-2-yl)-1,3,4-thiadiazol-2-yl]phenyl}pyrrolo[2,1-f][1,2,4]triazin-4-amine'>YFV</scene></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=8gmc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8gmc OCA], [https://pdbe.org/8gmc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8gmc RCSB], [https://www.ebi.ac.uk/pdbsum/8gmc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8gmc ProSAT]</span></td></tr>
</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 ==
Adaptor protein 2-associated kinase 1 (AAK1) is a member of the Ark1/Prk1 family of serine/threonine kinases and plays a role in modulating receptor endocytosis. AAK1 was identified as a potential therapeutic target for the treatment of neuropathic pain when it was shown that AAK1 knock out (KO) mice had a normal response to the acute pain phase of the mouse formalin model, but a reduced response to the persistent pain phase. Herein we report our early work investigating a series of pyrrolo[2,1-f][1,2,4]triazines as part of our efforts to recapitulate this KO phenotype with a potent, small molecule inhibitor of AAK1. The synthesis, structure-activity relationships (SAR), and in vivo evaluation of these AAK1 inhibitors is described.

Discovery of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of adaptor protein 2-associated kinase 1 for the treatment of pain.,Dzierba CD, Dasgupta B, Karageorge G, Kostich W, Hamman B, Allen J, Esposito KM, Padmanabha R, Grace J, Lentz K, Morrison J, Morgan D, Easton A, Bourin C, Browning MR, Rajamani R, Good A, Parker DD, Muckelbauer JK, Khan J, Camac D, Ghosh K, Halan V, Lippy JS, Santone KS, Denton RR, Westphal R, Bristow LJ, Conway CM, Bronson JJ, Macor JE Med Chem Res. 2023 Jun 3:1-7. doi: 10.1007/s00044-023-03079-x. PMID:37362320<ref>PMID:37362320</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8gmc" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Muckelbauer JK]]