7rj8

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Current revision (07:20, 3 April 2024) (edit) (undo)
 
Line 3: Line 3:
<StructureSection load='7rj8' size='340' side='right'caption='[[7rj8]], [[Resolution|resolution]] 2.59&Aring;' scene=''>
<StructureSection load='7rj8' size='340' side='right'caption='[[7rj8]], [[Resolution|resolution]] 2.59&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
-
<table><tr><td colspan='2'>[[7rj8]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7RJ8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RJ8 FirstGlance]. <br>
+
<table><tr><td colspan='2'>[[7rj8]] 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=7RJ8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RJ8 FirstGlance]. <br>
-
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5QI:N-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-D-leucinamide'>5QI</scene>, <scene name='pdbligand=PG6:1-(2-METHOXY-ETHOXY)-2-{2-[2-(2-METHOXY-ETHOXY]-ETHOXY}-ETHANE'>PG6</scene>, <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>
+
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.59&#8491;</td></tr>
-
<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>
+
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5QI:N-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-D-leucinamide'>5QI</scene>, <scene name='pdbligand=PG6:1-(2-METHOXY-ETHOXY)-2-{2-[2-(2-METHOXY-ETHOXY]-ETHOXY}-ETHANE'>PG6</scene>, <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=7rj8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rj8 OCA], [https://pdbe.org/7rj8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rj8 RCSB], [https://www.ebi.ac.uk/pdbsum/7rj8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rj8 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=7rj8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rj8 OCA], [https://pdbe.org/7rj8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rj8 RCSB], [https://www.ebi.ac.uk/pdbsum/7rj8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rj8 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
-
[[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]
+
[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]
-
<div style="background-color:#fffaf0;">
+
-
== Publication Abstract from PubMed ==
+
-
Adaptor protein 2-associated kinase 1 (AAK1) is a serine/threonine kinase that was identified as a therapeutic target for the potential treatment of neuropathic pain. Inhibition of AAK1 in the central nervous system, particularly within the spinal cord, was found to be the relevant site for achieving an antinociceptive effect. We previously reported that compound 7 is a brain-penetrant, AAK1 inhibitor that showed efficacy in animal models for neuropathic pain. One approach we took to improve upon the potency of 7 involved tying the amide back into the neighboring phenyl ring to form a bicyclic heterocycle. Investigation of the structure-activity relationships (SARs) of substituents on the resultant quinazoline and quinoline ring systems led to the identification of (S)-31, a brain-penetrant, AAK1-selective inhibitor with improved enzyme and cellular potency compared to 7. The synthesis, SAR, and in vivo evaluation of a series of quinazoline and quinoline-based AAK1 inhibitors are described herein.
+
-
 
+
-
Bicyclic Heterocyclic Replacement of an Aryl Amide Leading to Potent and Kinase-Selective Adaptor Protein 2-Associated Kinase 1 Inhibitors.,Hartz RA, Ahuja VT, Nara SJ, Kumar CMV, Manepalli RKVLP, Sarvasiddhi SK, Honkhambe S, Patankar V, Dasgupta B, Rajamani R, Muckelbauer JK, Camac DM, Ghosh K, Pokross M, Kiefer SE, Brown JM, Hunihan L, Gulianello M, Lewis M, Lippy JS, Surti N, Hamman BD, Allen J, Kostich WA, Bronson JJ, Macor JE, Dzierba CD J Med Chem. 2022 Feb 16. doi: 10.1021/acs.jmedchem.1c01966. PMID:35171586<ref>PMID:35171586</ref>
+
-
 
+
-
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+
-
</div>
+
-
<div class="pdbe-citations 7rj8" style="background-color:#fffaf0;"></div>
+
-
== References ==
+
-
<references/>
+
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
-
[[Category: Non-specific serine/threonine protein kinase]]
+
[[Category: Mus musculus]]
-
[[Category: Muckelbauer, J]]
+
[[Category: Muckelbauer J]]
-
[[Category: Pokross, M]]
+
[[Category: Pokross M]]
-
[[Category: Aak1]]
+
-
[[Category: Kinase]]
+
-
[[Category: Ligand]]
+
-
[[Category: Transferase]]
+
-
[[Category: Transferase-transferase inhibitor complex]]
+

Current revision

CRYSTAL STRUCTURE OF AP2 ASSOCIATED KINASE 1 ISOFORM 1 COMPLEXED WITH LIGAND (2R)-2-AMINO-N-[3-(DIFLUOROM ETHOXY)-4-(1,3-OXAZOL-5-YL)PHENYL]-4-METHYLPENTANAMIDE

PDB ID 7rj8

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7rj8"
Personal tools