5ia2: Difference between revisions

From Proteopedia
Jump to navigation Jump to search
← Older edit
No edit summary
No edit summary
 
Line 3: Line 3:
<StructureSection load='5ia2' size='340' side='right'caption='[[5ia2]], [[Resolution|resolution]] 1.62&Aring;' scene=''>
<StructureSection load='5ia2' size='340' side='right'caption='[[5ia2]], [[Resolution|resolution]] 1.62&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5ia2]] 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=5IA2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5IA2 FirstGlance]. <br>
<table><tr><td colspan='2'>[[5ia2]] 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=5IA2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5IA2 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=L66:7-(5-HYDROXY-2-METHYLPHENYL)-8-(2-METHOXYPHENYL)-1-METHYL-1H-IMIDAZO[2,1-F]PURINE-2,4(3H,8H)-DIONE'>L66</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]] 1.619&#8491;</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='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=L66:7-(5-HYDROXY-2-METHYLPHENYL)-8-(2-METHOXYPHENYL)-1-METHYL-1H-IMIDAZO[2,1-F]PURINE-2,4(3H,8H)-DIONE'>L66</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=5ia2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ia2 OCA], [https://pdbe.org/5ia2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ia2 RCSB], [https://www.ebi.ac.uk/pdbsum/5ia2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ia2 ProSAT]</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=5ia2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ia2 OCA], [http://pdbe.org/5ia2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ia2 RCSB], [http://www.ebi.ac.uk/pdbsum/5ia2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ia2 ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== 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>
[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 ==
== 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>
[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;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
Line 24: Line 23:


==See Also==
==See Also==
*[[Ephrin receptor|Ephrin receptor]]
*[[Ephrin receptor 3D structures|Ephrin receptor 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Receptor protein-tyrosine kinase]]
[[Category: Gande SL]]
[[Category: Gande, S L]]
[[Category: Heinzlmeir S]]
[[Category: Heinzlmeir, S]]
[[Category: Kudlinzki D]]
[[Category: Kudlinzki, D]]
[[Category: Kuester B]]
[[Category: Kuester, B]]
[[Category: Linhard VL]]
[[Category: Linhard, V L]]
[[Category: Medard G]]
[[Category: Medard, G]]
[[Category: Saxena K]]
[[Category: Saxena, K]]
[[Category: Schwalbe H]]
[[Category: Schwalbe, H]]
[[Category: Sreeramulu S]]
[[Category: Sreeramulu, S]]
[[Category: Atp-binding]]
[[Category: Receptor]]
[[Category: Transferase]]
[[Category: Tyrosine-protein kinase]]

Latest revision as of 16:43, 30 August 2023

Crystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase with compound 66Crystal Structure of Ephrin A2 (EphA2) Receptor Protein Kinase with compound 66

Structural highlights

5ia2 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.619Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

EPHA2_HUMAN Genetic variations in EPHA2 are the cause of susceptibility to cataract cortical age-related type 2 (ARCC2) [MIM: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.[1] [2] Defects in EPHA2 are the cause of cataract posterior polar type 1 (CTPP1) [MIM:116600. A subcapsular opacity, usually disk-shaped, located at the back of the lens. It can have a marked effect on visual acuity.[3] [4] [5] [6] Note=Overexpressed in several cancer types and promotes malignancy.[7]

Function

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.[8] [9] [10] [11] [12] [13]

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[14]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Miao H, Li DQ, Mukherjee A, Guo H, Petty A, Cutter J, Basilion JP, Sedor J, Wu J, Danielpour D, Sloan AE, Cohen ML, Wang B. EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt. Cancer Cell. 2009 Jul 7;16(1):9-20. doi: 10.1016/j.ccr.2009.04.009. PMID:19573808 doi:10.1016/j.ccr.2009.04.009
  2. ↑ Jun G, Guo H, Klein BE, Klein R, Wang JJ, Mitchell P, Miao H, Lee KE, Joshi T, Buck M, Chugha P, Bardenstein D, Klein AP, Bailey-Wilson JE, Gong X, Spector TD, Andrew T, Hammond CJ, Elston RC, Iyengar SK, Wang B. EPHA2 is associated with age-related cortical cataract in mice and humans. PLoS Genet. 2009 Jul;5(7):e1000584. doi: 10.1371/journal.pgen.1000584. Epub 2009 , Jul 31. PMID:19649315 doi:10.1371/journal.pgen.1000584
  3. ↑ Miao H, Li DQ, Mukherjee A, Guo H, Petty A, Cutter J, Basilion JP, Sedor J, Wu J, Danielpour D, Sloan AE, Cohen ML, Wang B. EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt. Cancer Cell. 2009 Jul 7;16(1):9-20. doi: 10.1016/j.ccr.2009.04.009. PMID:19573808 doi:10.1016/j.ccr.2009.04.009
  4. ↑ Shiels A, Bennett TM, Knopf HL, Maraini G, Li A, Jiao X, Hejtmancik JF. The EPHA2 gene is associated with cataracts linked to chromosome 1p. Mol Vis. 2008;14:2042-55. Epub 2008 Nov 12. PMID:19005574
  5. ↑ Zhang T, Hua R, Xiao W, Burdon KP, Bhattacharya SS, Craig JE, Shang D, Zhao X, Mackey DA, Moore AT, Luo Y, Zhang J, Zhang X. Mutations of the EPHA2 receptor tyrosine kinase gene cause autosomal dominant congenital cataract. Hum Mutat. 2009 May;30(5):E603-11. doi: 10.1002/humu.20995. PMID:19306328 doi:10.1002/humu.20995
  6. ↑ Park JE, Son AI, Hua R, Wang L, Zhang X, Zhou R. Human cataract mutations in EPHA2 SAM domain alter receptor stability and function. PLoS One. 2012;7(5):e36564. doi: 10.1371/journal.pone.0036564. Epub 2012 May 3. PMID:22570727 doi:10.1371/journal.pone.0036564
  7. ↑ Miao H, Li DQ, Mukherjee A, Guo H, Petty A, Cutter J, Basilion JP, Sedor J, Wu J, Danielpour D, Sloan AE, Cohen ML, Wang B. EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt. Cancer Cell. 2009 Jul 7;16(1):9-20. doi: 10.1016/j.ccr.2009.04.009. PMID:19573808 doi:10.1016/j.ccr.2009.04.009
  8. ↑ Miao H, Burnett E, Kinch M, Simon E, Wang B. Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation. Nat Cell Biol. 2000 Feb;2(2):62-9. PMID:10655584 doi:10.1038/35000008
  9. ↑ Tanaka M, Kamata R, Sakai R. EphA2 phosphorylates the cytoplasmic tail of Claudin-4 and mediates paracellular permeability. J Biol Chem. 2005 Dec 23;280(51):42375-82. Epub 2005 Oct 18. PMID:16236711 doi:10.1074/jbc.M503786200
  10. ↑ Zhang G, Njauw CN, Park JM, Naruse C, Asano M, Tsao H. EphA2 is an essential mediator of UV radiation-induced apoptosis. Cancer Res. 2008 Mar 15;68(6):1691-6. doi: 10.1158/0008-5472.CAN-07-2372. PMID:18339848 doi:10.1158/0008-5472.CAN-07-2372
  11. ↑ Miao H, Li DQ, Mukherjee A, Guo H, Petty A, Cutter J, Basilion JP, Sedor J, Wu J, Danielpour D, Sloan AE, Cohen ML, Wang B. EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt. Cancer Cell. 2009 Jul 7;16(1):9-20. doi: 10.1016/j.ccr.2009.04.009. PMID:19573808 doi:10.1016/j.ccr.2009.04.009
  12. ↑ Hiramoto-Yamaki N, Takeuchi S, Ueda S, Harada K, Fujimoto S, Negishi M, Katoh H. Ephexin4 and EphA2 mediate cell migration through a RhoG-dependent mechanism. J Cell Biol. 2010 Aug 9;190(3):461-77. doi: 10.1083/jcb.201005141. Epub 2010 Aug , 2. PMID:20679435 doi:10.1083/jcb.201005141
  13. ↑ Lin S, Gordon K, Kaplan N, Getsios S. Ligand targeting of EphA2 enhances keratinocyte adhesion and differentiation via desmoglein 1. Mol Biol Cell. 2010 Nov 15;21(22):3902-14. doi: 10.1091/mbc.E10-03-0242. Epub, 2010 Sep 22. PMID:20861311 doi:10.1091/mbc.E10-03-0242
  14. ↑ 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. Chemical proteomics and structural biology define EPHA2 inhibition by clinical kinase drugs. ACS Chem Biol. 2016 Oct 21. PMID:27768280 doi:http://dx.doi.org/10.1021/acschembio.6b00709

5ia2, resolution 1.62Å

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA
Retrieved from "https://proteopedia.openfox.io/wiki/index.php?title=5ia2&oldid=3858902"