7ofv
From Proteopedia
(Difference between revisions)
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| - | ==== | + | ==NMR-guided design of potent and selective EphA4 agonistic ligands== |
| - | <StructureSection load='7ofv' size='340' side='right'caption='[[7ofv]]' scene=''> | + | <StructureSection load='7ofv' size='340' side='right'caption='[[7ofv]], [[Resolution|resolution]] 1.43Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7ofv]] 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=7OFV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OFV FirstGlance]. <br> |
| - | </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=7ofv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ofv OCA], [https://pdbe.org/7ofv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ofv RCSB], [https://www.ebi.ac.uk/pdbsum/7ofv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ofv ProSAT]</span></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]] 1.43Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4PQ:5-HYDROXY-L-TRYPTOPHAN'>4PQ</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=BIF:(R)-2-AMINO-3-(4-PHENYLCYCLOHEXYL)PROPANOIC+ACID'>BIF</scene>, <scene name='pdbligand=HRG:L-HOMOARGININE'>HRG</scene>, <scene name='pdbligand=VDK:[(1S,3S)-3-carboxycyclohexyl]azanium'>VDK</scene>, <scene name='pdbligand=VDQ:4-morpholin-4-ylaniline'>VDQ</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=7ofv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ofv OCA], [https://pdbe.org/7ofv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ofv RCSB], [https://www.ebi.ac.uk/pdbsum/7ofv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ofv ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/EPHA4_HUMAN EPHA4_HUMAN] Receptor tyrosine kinase which binds 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, it has the unique property among Eph receptors to bind and to be physiologically activated by both GPI-anchored ephrin-A and transmembrane ephrin-B ligands including EFNA1 and EFNB3. Upon activation by ephrin ligands, modulates cell morphology and integrin-dependent cell adhesion through regulation of the Rac, Rap and Rho GTPases activity. Plays an important role in the development of the nervous system controlling different steps of axonal guidance including the establishment of the corticospinal projections. May also control the segregation of motor and sensory axons during neuromuscular circuit development. Beside its role in axonal guidance plays a role in synaptic plasticity. Activated by EFNA1 phosphorylates CDK5 at 'Tyr-15' which in turn phosphorylates NGEF regulating RHOA and dendritic spine morphogenesis. In the nervous system, plays also a role in repair after injury preventing axonal regeneration and in angiogenesis playing a role in central nervous system vascular formation. Additionally, its promiscuity makes it available to participate in a variety of cell-cell signaling regulating for instance the development of the thymic epithelium.<ref>PMID:17143272</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | In this paper, we applied an innovative nuclear magnetic resonance (NMR)-guided screening and ligand design approach, named focused high-throughput screening by NMR (fHTS by NMR), to derive potent, low-molecular-weight ligands capable of mimicking interactions elicited by ephrin ligands on the receptor tyrosine kinase EphA4. The agents bind with nanomolar affinity, trigger receptor activation in cellular assays with motor neurons, and provide remarkable motor neuron protection from amyotrophic lateral sclerosis (ALS) patient-derived astrocytes. Structural studies on the complex between EphA4 ligand-binding domain and a most active agent provide insights into the mechanism of the agents at a molecular level. Together with preliminary in vivo pharmacology studies, the data form a strong foundation for the translation of these agents for the treatment of ALS and potentially other human diseases. | ||
| + | |||
| + | NMR-Guided Design of Potent and Selective EphA4 Agonistic Ligands.,Baggio C, Kulinich A, Dennys CN, Rodrigo R, Meyer K, Ethell I, Pellecchia M J Med Chem. 2021 Aug 12;64(15):11229-11246. doi: 10.1021/acs.jmedchem.1c00608. , Epub 2021 Jul 22. PMID:34293864<ref>PMID:34293864</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7ofv" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Ephrin receptor 3D structures|Ephrin receptor 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: | + | [[Category: Synthetic construct]] |
| + | [[Category: Baggio C]] | ||
| + | [[Category: Craig TK]] | ||
| + | [[Category: Ganichkin OM]] | ||
| + | [[Category: Pellecchia M]] | ||
Current revision
NMR-guided design of potent and selective EphA4 agonistic ligands
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