8bin
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | The entry | + | ==Crystal structure of human Ephrin type-A receptor 2 (EPHA2) Kinase domain in complex with MR21== |
| + | <StructureSection load='8bin' size='340' side='right'caption='[[8bin]], [[Resolution|resolution]] 1.50Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8bin]] is a 1 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=8BIN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8BIN 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]] 1.5Å</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=QRR:8-(4-azanylbutyl)-6-(2-chlorophenyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one'>QRR</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=8bin FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8bin OCA], [https://pdbe.org/8bin PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8bin RCSB], [https://www.ebi.ac.uk/pdbsum/8bin PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8bin ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [https://www.uniprot.org/uniprot/EPHA2_HUMAN EPHA2_HUMAN] Genetic variations in EPHA2 are the cause of susceptibility to cataract cortical age-related type 2 (ARCC2) [MIM:[https://omim.org/entry/613020 613020]. A developmental punctate opacity common in the cortex and present in most lenses. The cataract is white or cerulean, increases in number with age, but rarely affects vision.<ref>PMID:19573808</ref> <ref>PMID:19649315</ref> Defects in EPHA2 are the cause of cataract posterior polar type 1 (CTPP1) [MIM:[https://omim.org/entry/116600 116600]. A subcapsular opacity, usually disk-shaped, located at the back of the lens. It can have a marked effect on visual acuity.<ref>PMID:19573808</ref> <ref>PMID:19005574</ref> <ref>PMID:19306328</ref> <ref>PMID:22570727</ref> Note=Overexpressed in several cancer types and promotes malignancy.<ref>PMID:19573808</ref> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/EPHA2_HUMAN EPHA2_HUMAN] Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Activated by the ligand ephrin-A1/EFNA1 regulates migration, integrin-mediated adhesion, proliferation and differentiation of cells. Regulates cell adhesion and differentiation through DSG1/desmoglein-1 and inhibition of the ERK1/ERK2 (MAPK3/MAPK1, respectively) signaling pathway. May also participate in UV radiation-induced apoptosis and have a ligand-independent stimulatory effect on chemotactic cell migration. During development, may function in distinctive aspects of pattern formation and subsequently in development of several fetal tissues. Involved for instance in angiogenesis, in early hindbrain development and epithelial proliferation and branching morphogenesis during mammary gland development. Engaged by the ligand ephrin-A5/EFNA5 may regulate lens fiber cells shape and interactions and be important for lens transparency development and maintenance. With ephrin-A2/EFNA2 may play a role in bone remodeling through regulation of osteoclastogenesis and osteoblastogenesis.<ref>PMID:10655584</ref> <ref>PMID:16236711</ref> <ref>PMID:18339848</ref> <ref>PMID:19573808</ref> <ref>PMID:20679435</ref> <ref>PMID:20861311</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Macrocyclization of acyclic compounds is a powerful strategy for improving inhibitor potency and selectivity. Here we have optimized 2-aminopyrimidine-based macrocycles to use these compounds as chemical tools for the ephrin kinase family. Starting with a promiscuous macrocyclic inhibitor, 6, we performed a structure-guided activity relationship and selectivity study using a panel of over 100 kinases. The crystal structure of EPHA2 in complex with the developed macrocycle 23 provided a basis for further optimization by specifically targeting the back pocket, resulting in compound 55, a potent inhibitor of EPHA2/A4 and GAK. Subsequent front-pocket derivatization resulted in an interesting in cellulo selectivity profile, favoring EPHA4 over the other ephrin receptor kinase family members. The dual EPHA2/A4 and GAK inhibitor 55 prevented dengue virus infection of Huh7 liver cells. However, further investigations are needed to determine whether this was a compound-specific effect or target-related. | ||
| - | + | Back-Pocket Optimization of 2-Aminopyrimidine-Based Macrocycles Leads to Potent EPHA2/GAK Kinase Inhibitors.,Gerninghaus J, Zhubi R, Kramer A, Karim M, Tran DHN, Joerger AC, Schreiber C, Berger LM, Berger BT, Ehret TAL, Elson L, Lenz C, Saxena K, Muller S, Einav S, Knapp S, Hanke T J Med Chem. 2024 Jul 19. doi: 10.1021/acs.jmedchem.4c00411. PMID:39028937<ref>PMID:39028937</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 8bin" style="background-color:#fffaf0;"></div> |
| - | [[Category: Knapp | + | |
| - | [[Category: | + | ==See Also== |
| - | [[Category: | + | *[[Ephrin receptor 3D structures|Ephrin receptor 3D structures]] |
| - | [[Category: | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Knapp S]] | ||
| + | [[Category: Kraemer A]] | ||
| + | [[Category: Rak M]] | ||
| + | [[Category: Zhubi R]] | ||
Current revision
Crystal structure of human Ephrin type-A receptor 2 (EPHA2) Kinase domain in complex with MR21
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Categories: Homo sapiens | Large Structures | Knapp S | Kraemer A | Rak M | Zhubi R
