4g2f: Difference between revisions
No edit summary |
No edit summary |
||
| (5 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
==Human EphA3 kinase domain in complex with compound 7== | |||
<StructureSection load='4g2f' size='340' side='right'caption='[[4g2f]], [[Resolution|resolution]] 1.70Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4g2f]] 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=4G2F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4G2F 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]] 1.699Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C07:1-AMINO-5-(5-HYDROXY-2-METHYLPHENYL)-7,8,9,10-TETRAHYDROPYRIMIDO[4,5-C]ISOQUINOLIN-6(5H)-ONE'>C07</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=4g2f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4g2f OCA], [https://pdbe.org/4g2f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4g2f RCSB], [https://www.ebi.ac.uk/pdbsum/4g2f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4g2f ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/EPHA3_HUMAN EPHA3_HUMAN] Defects in EPHA3 may be a cause of colorectal cancer (CRC) [MIM:[https://omim.org/entry/114500 114500]. | |||
== Function == | |||
[https://www.uniprot.org/uniprot/EPHA3_HUMAN EPHA3_HUMAN] Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin 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. Highly promiscuous for ephrin-A ligands it binds preferentially EFNA5. Upon activation by EFNA5 regulates cell-cell adhesion, cytoskeletal organization and cell migration. Plays a role in cardiac cells migration and differentiation and regulates the formation of the atrioventricular canal and septum during development probably through activation by EFNA1. Involved in the retinotectal mapping of neurons. May also control the segregation but not the guidance of motor and sensory axons during neuromuscular circuit development.<ref>PMID:11870224</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
We have discovered a novel chemical class of inhibitors of the EphB4 tyrosine kinase by fragment-based high-throughput docking followed by explicit solvent molecular dynamics simulations for assessment of the binding mode. The synthesis of a single derivative (compound 7) of the hit identified in silico has resulted in an improvement of the inhibitory potency in an enzymatic assay from 8.4 muM to 160 nM and a ligand efficiency of 0.39 kcal/mol per non-hydrogen atom. Such remarkable improvement in affinity is due to an additional hydroxyl group involved in two favorable (buried) hydrogen bonds as predicted by molecular dynamics and validated by the crystal structure of the complex with EphA3 solved at 1.7 A resolution. | |||
Discovery of a novel chemotype of tyrosine kinase inhibitors by fragment-based docking and molecular dynamics.,Zhao H, Dong J, Lafleur K, Nevado C, Caflisch A ACS Med Chem Lett. 2012 Aug 23;3(10):834-8. doi: 10.1021/ml3001984. eCollection, 2012 Oct 11. PMID:24900387<ref>PMID:24900387</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4g2f" style="background-color:#fffaf0;"></div> | |||
== | ==See Also== | ||
[[ | *[[Ephrin receptor 3D structures|Ephrin receptor 3D structures]] | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Caflisch | [[Category: Caflisch A]] | ||
[[Category: Dong | [[Category: Dong J]] | ||
Latest revision as of 16:55, 8 November 2023
Human EphA3 kinase domain in complex with compound 7Human EphA3 kinase domain in complex with compound 7
Structural highlights
DiseaseEPHA3_HUMAN Defects in EPHA3 may be a cause of colorectal cancer (CRC) [MIM:114500. FunctionEPHA3_HUMAN Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin 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. Highly promiscuous for ephrin-A ligands it binds preferentially EFNA5. Upon activation by EFNA5 regulates cell-cell adhesion, cytoskeletal organization and cell migration. Plays a role in cardiac cells migration and differentiation and regulates the formation of the atrioventricular canal and septum during development probably through activation by EFNA1. Involved in the retinotectal mapping of neurons. May also control the segregation but not the guidance of motor and sensory axons during neuromuscular circuit development.[1] Publication Abstract from PubMedWe have discovered a novel chemical class of inhibitors of the EphB4 tyrosine kinase by fragment-based high-throughput docking followed by explicit solvent molecular dynamics simulations for assessment of the binding mode. The synthesis of a single derivative (compound 7) of the hit identified in silico has resulted in an improvement of the inhibitory potency in an enzymatic assay from 8.4 muM to 160 nM and a ligand efficiency of 0.39 kcal/mol per non-hydrogen atom. Such remarkable improvement in affinity is due to an additional hydroxyl group involved in two favorable (buried) hydrogen bonds as predicted by molecular dynamics and validated by the crystal structure of the complex with EphA3 solved at 1.7 A resolution. Discovery of a novel chemotype of tyrosine kinase inhibitors by fragment-based docking and molecular dynamics.,Zhao H, Dong J, Lafleur K, Nevado C, Caflisch A ACS Med Chem Lett. 2012 Aug 23;3(10):834-8. doi: 10.1021/ml3001984. eCollection, 2012 Oct 11. PMID:24900387[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||