7lvh

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<StructureSection load='7lvh' size='340' side='right'caption='[[7lvh]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
<StructureSection load='7lvh' size='340' side='right'caption='[[7lvh]], [[Resolution|resolution]] 2.65&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[7lvh]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LVH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LVH FirstGlance]. <br>
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<table><tr><td colspan='2'>[[7lvh]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LVH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LVH FirstGlance]. <br>
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</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=YFS:N-[3-methoxy-4-(1,3-oxazol-5-yl)phenyl]-D-leucinamide'>YFS</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>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.65&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Aak1, Kiaa1048 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
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<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=YFS:N-[3-methoxy-4-(1,3-oxazol-5-yl)phenyl]-D-leucinamide'>YFS</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>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7lvh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lvh OCA], [https://pdbe.org/7lvh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lvh RCSB], [https://www.ebi.ac.uk/pdbsum/7lvh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lvh ProSAT]</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=7lvh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lvh OCA], [https://pdbe.org/7lvh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lvh RCSB], [https://www.ebi.ac.uk/pdbsum/7lvh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lvh ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[https://www.uniprot.org/uniprot/AAK1_MOUSE AAK1_MOUSE]] 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. Preferentially, may phosphorylate substrates on threonine residues. 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.[UniProtKB:Q2M2I8]
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[https://www.uniprot.org/uniprot/AAK1_MOUSE AAK1_MOUSE] 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. Preferentially, may phosphorylate substrates on threonine residues. 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.[UniProtKB:Q2M2I8]
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Effective treatment of chronic pain, in particular neuropathic pain, without the side effects that often accompany currently available treatment options is an area of significant unmet medical need. A phenotypic screen of mouse gene knockouts led to the discovery that adaptor protein 2-associated kinase 1 (AAK1) is a potential therapeutic target for neuropathic pain. The synthesis and optimization of structure-activity relationships of a series of aryl amide-based AAK1 inhibitors led to the identification of 59, a brain penetrant, AAK1-selective inhibitor that proved to be a valuable tool compound. Compound 59 was evaluated in mice for the inhibition of mu2 phosphorylation. Studies conducted with 59 in pain models demonstrated that this compound was efficacious in the phase II formalin model for persistent pain and the chronic-constriction-injury-induced model for neuropathic pain in rats. These results suggest that AAK1 inhibition is a promising approach for the treatment of neuropathic pain.
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Discovery, Structure-Activity Relationships, and In Vivo Evaluation of Novel Aryl Amides as Brain Penetrant Adaptor Protein 2-Associated Kinase 1 (AAK1) Inhibitors for the Treatment of Neuropathic Pain.,Hartz RA, Ahuja VT, Nara SJ, Kumar CMV, Brown JM, Bristow LJ, Rajamani R, Muckelbauer JK, Camac D, Kiefer SE, Hunihan L, Gulianello M, Lewis M, Easton A, Lippy JS, Surti N, Pattipati SN, Dokania M, Elavazhagan S, Dandapani K, Hamman BD, Allen J, Kostich W, Bronson JJ, Macor JE, Dzierba CD J Med Chem. 2021 Jul 16. doi: 10.1021/acs.jmedchem.1c00472. PMID:34270254<ref>PMID:34270254</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 7lvh" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Lk3 transgenic mice]]
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[[Category: Mus musculus]]
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[[Category: Non-specific serine/threonine protein kinase]]
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[[Category: Muckelbauer JK]]
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[[Category: Muckelbauer, J K]]
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[[Category: Aak1]]
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[[Category: Kinase]]
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[[Category: Ligand]]
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[[Category: Transferase]]
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[[Category: Transferase-transferase inhibitor complex]]
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Current revision

CRYSTAL STRUCTURE OF AP2 ASSOCIATED KINASE 1 ISOFORM 1 COMPLEXED WITH LIGAND N-[3-METHOXY-4-(1,3-OXAZOL-5-YL)PHENYL]-3-(PROPAN-2-YL)PIPERIDINE-2-CARBOXAMIDE

PDB ID 7lvh

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