6rw2: Difference between revisions

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<StructureSection load='6rw2' size='340' side='right'caption='[[6rw2]], [[Resolution|resolution]] 2.26&Aring;' scene=''>
<StructureSection load='6rw2' size='340' side='right'caption='[[6rw2]], [[Resolution|resolution]] 2.26&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6rw2]] is a 2 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=6RW2 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6RW2 FirstGlance]. <br>
<table><tr><td colspan='2'>[[6rw2]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RW2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6RW2 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=29N:1,1,1-(1,3,5-TRIAZINANE-1,3,5-TRIYL)TRIPROPAN-1-ONE'>29N</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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]] 2.26&#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=29N:1,1,1-(1,3,5-TRIAZINANE-1,3,5-TRIYL)TRIPROPAN-1-ONE'>29N</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=6rw2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rw2 OCA], [https://pdbe.org/6rw2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6rw2 RCSB], [https://www.ebi.ac.uk/pdbsum/6rw2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6rw2 ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6rw2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rw2 OCA], [http://pdbe.org/6rw2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6rw2 RCSB], [http://www.ebi.ac.uk/pdbsum/6rw2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6rw2 ProSAT]</span></td></tr>
</table>
</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;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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</div>
</div>
<div class="pdbe-citations 6rw2" style="background-color:#fffaf0;"></div>
<div class="pdbe-citations 6rw2" style="background-color:#fffaf0;"></div>
==See Also==
*[[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: Synthetic construct]]
[[Category: Brown, D G]]
[[Category: Brown DG]]
[[Category: Chen, L]]
[[Category: Chen L]]
[[Category: Schroeder, S]]
[[Category: Schroeder S]]
[[Category: Complex]]
[[Category: Epha2]]
[[Category: Inhibitor]]
[[Category: Signaling protein]]

Latest revision as of 11:18, 17 October 2024

Bicycle Toxin Conjugate bound to EphA2Bicycle Toxin Conjugate bound to EphA2

Structural highlights

6rw2 is a 2 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.26Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

Bicycles are constrained bicyclic peptides that represent a promising binding modality for use in targeted drug conjugates. A phage display screen against EphA2, a receptor tyrosine kinase highly expressed in a number of solid tumors, identified a number of Bicycle families with low nanomolar affinity. A Bicycle toxin conjugate (BTC) was generated by derivatization of one of these Bicycles with the potent cytotoxin DM1 via a cleavable linker. This BTC demonstrated potent antitumor activity in vivo but was poorly tolerated, which was hypothesized to be the result of undesired liver uptake caused by poor physicochemical properties. Chemical optimization of a second Bicycle, guided by structural biology, provided a high affinity, metabolically stable Bicycle with improved physicochemical properties. A BTC incorporating this Bicycle also demonstrated potent antitumor activity and was very well tolerated when compared to the initial BTC. Phage display selection followed by chemical optimization of Bicycles can deliver potent drug conjugates with favorable pharmaceutical properties.

Identification and Optimization of EphA2-Selective Bicycles for the Delivery of Cytotoxic Payloads.,Mudd GE, Brown A, Chen L, van Rietschoten K, Watcham S, Teufel DP, Pavan S, Lani R, Huxley P, Bennett GS J Med Chem. 2020 Apr 2. doi: 10.1021/acs.jmedchem.9b02129. PMID:32202781[1]

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

See Also

References

  1. ↑ Mudd GE, Brown A, Chen L, van Rietschoten K, Watcham S, Teufel DP, Pavan S, Lani R, Huxley P, Bennett GS. Identification and Optimization of EphA2-Selective Bicycles for the Delivery of Cytotoxic Payloads. J Med Chem. 2020 Apr 2. doi: 10.1021/acs.jmedchem.9b02129. PMID:32202781 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b02129

6rw2, resolution 2.26Å

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