View source for 5ia4


==Crystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase with foretinib (XL880)==
<StructureSection load='5ia4' size='340' side='right'caption='[[5ia4]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5ia4]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IA4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5IA4 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=88Z:N-(3-FLUORO-4-{[6-METHOXY-7-(3-MORPHOLIN-4-YLPROPOXY)QUINOLIN-4-YL]OXY}PHENYL)-N-(4-FLUOROPHENYL)CYCLOPROPANE-1,1-DICARBOXAMIDE'>88Z</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">EPHA2, ECK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ia4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ia4 OCA], [http://pdbe.org/5ia4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ia4 RCSB], [http://www.ebi.ac.uk/pdbsum/5ia4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ia4 ProSAT]</span></td></tr>
</table>
== Disease ==
[[http://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:[http://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:[http://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 ==
[[http://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 ==
The receptor tyrosine kinase EPHA2 (Ephrin type-A receptor 2) plays important roles in oncogenesis, metastasis and treatment resistance yet therapeutic targeting, drug discovery or investigation of EPHA2 biology is hampered by the lack of appropriate inhibitors and structural information. Here, we used chemical proteomics to survey 235 clinical kinase inhibitors for their kinase selectivity and identified 24 drugs with sub-micromolar affinities for EPHA2. NMR-based conformational dynamics together with nine new co-crystal structures delineated drug-EPHA2 interactions in full detail. The combination of selectivity profiling, structure determination and kinome wide sequence alignment allowed the development of a classification system in which amino acids in the drug binding site of EPHA2 are categorized into key, scaffold, potency and selectivity residues. This scheme should be generally applicable in kinase drug discovery and we anticipate that the provided information will greatly facilitate the development of selective EPHA2 inhibitors in particular and the repurposing of clinical kinase inhibitors in general.

Chemical proteomics and structural biology define EPHA2 inhibition by clinical kinase drugs.,Heinzlmeir S, Kudlinzki D, Sreeramulu S, Klaeger S, Gande SL, Linhard V, Wilhelm M, Qiao H, Helm D, Ruprecht B, Saxena K, Medard G, Schwalbe H, Kuster B ACS Chem Biol. 2016 Oct 21. PMID:27768280<ref>PMID:27768280</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5ia4" style="background-color:#fffaf0;"></div>

==See Also==
*[[Ephrin receptor|Ephrin receptor]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Receptor protein-tyrosine kinase]]
[[Category: Gande, S L]]
[[Category: Heinzlmeir, S]]
[[Category: Kudlinzki, D]]
[[Category: Kuester, B]]
[[Category: Linhard, V L]]
[[Category: Medard, G]]
[[Category: Saxena, K]]
[[Category: Schwalbe, H]]
[[Category: Sreeramulu, S]]
[[Category: Atp-binding]]
[[Category: Receptor]]
[[Category: Transferase]]
[[Category: Tyrosine-protein kinase]]