Crystal structure and NMR binding reveal that two small molecule antagonists target the high affinity ephrin-binding channel of the EphA4 receptor.

The Journal of Biological Chemistry
Haina QinJianxing Song

Abstract

The Eph receptor tyrosine kinases regulate a variety of physiological and pathological processes not only during development but also in adult organs, and therefore they represent a promising class of drug targets. The EphA4 receptor plays important roles in the inhibition of the regeneration of injured axons, synaptic plasticity, platelet aggregation, and likely in certain types of cancer. Here we report the first crystal structure of the EphA4 ligand-binding domain, which adopts the same jellyroll beta-sandwich architecture as shown previously for EphB2 and EphB4. The similarity with EphB receptors is high in the core beta-stranded regions, whereas large variations exist in the loops, particularly the D-E and J-K loops, which form the high affinity ephrin binding channel. We also used isothermal titration calorimetry, NMR spectroscopy, and computational docking to characterize the binding to EphA4 of two small molecules, 4- and 5-(2,5 dimethyl-pyrrol-1-yl)-2-hydroxybenzoic acid which antagonize ephrin-induced effects in EphA4-expressing cells. We show that the two molecules bind to the EphA4 ligand-binding domain with K(d) values of 20.4 and 26.4 microm, respectively. NMR heteronuclear single quantum coherence titrations reve...Continue Reading

References

Nov 1, 1995·Journal of Biomolecular NMR·F DelaglioA Bax
Nov 1, 1995·Protein Science : a Publication of the Protein Society·C N PaceT Gray
Jun 11, 1997·International Journal of Cancer. Journal International Du Cancer·D J EastyD C Bennett
Oct 3, 1998·Acta Crystallographica. Section D, Biological Crystallography·A T BrüngerG L Warren
Sep 15, 2001·Nature·C A Cowan, M Henkemeyer
Jan 10, 2002·Nature·J P HimanenD B Nikolov
Apr 24, 2002·Seminars in Cell & Developmental Biology·Ralf H Adams
Oct 24, 2002·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsThomas C Terwilliger
Feb 13, 2003·Journal of the American Chemical Society·Cyril DominguezAlexandre M J J Bonvin
Apr 27, 2004·Nature Neuroscience·Juha-Pekka HimanenDimitar B Nikolov
Apr 29, 2004·Nature Neuroscience·Elena B Pasquale
Jun 15, 2004·Current Opinion in Neurobiology·Yu Yamaguchi, Elena B Pasquale
Jul 24, 2004·Acta Crystallographica. Section D, Biological Crystallography·Alexander W Schüttelkopf, Daan M F van Aalten
Sep 15, 2004·Current Opinion in Cell Biology·Rüdiger Klein
Nov 13, 2004·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Yona GoldshmitAnn M Turnley
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Feb 1, 2005·The American Journal of Pathology·Virginia J YaoRenata Pasqualini
Mar 15, 2005·The Journal of Biological Chemistry·Xiaoyuan Ran, Jianxing Song
Apr 5, 2005·Acta Crystallographica. Section D, Biological Crystallography·Airlie J McCoyRandy J Read
Jun 2, 2005·Nature Reviews. Molecular Cell Biology·Elena B Pasquale
Jul 5, 2005·Proceedings of the National Academy of Sciences of the United States of America·Nicolas PrévostLawrence F Brass
Jul 16, 2005·Proceedings of the National Academy of Sciences of the United States of America·M Douglas BensonLuis F Parada
Dec 7, 2005·Experimental Cell Research·Mélanie HéroultHellmut G Augustin
Oct 20, 2006·The Journal of Nutritional Biochemistry·Feng-Yao TangChung-Jin Shih
Apr 11, 2007·Trends in Cell Biology·Joaquim Egea, Rüdiger Klein
Aug 21, 2007·Current Pharmaceutical Design·J DuD W Sretavan
Sep 7, 2007·Proteins·Sjoerd J de VriesAlexandre M J J Bonvin
Sep 19, 2007·The Journal of Cell Biology·Caroline BourginElena B Pasquale
Oct 12, 2007·Current Opinion in Cell Biology·Juha-Pekka HimanenDimitar B Nikolov
Oct 30, 2007·Neuron·Liqun Luo, John G Flanagan
Dec 21, 2007·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Melanie RichterElena B Pasquale
Jan 10, 2008·Nature Biotechnology·Mazen W KaramanPatrick P Zarrinkar
Feb 19, 2008·Bioorganic & Medicinal Chemistry Letters·Yasushi MiyazakiGeoffrey W Mellor
Aug 30, 2008·The Journal of Biological Chemistry·Roberta NoberiniElena B Pasquale

❮ Previous
Next ❯

Citations

Feb 25, 2010·Nature Reviews. Cancer·Elena B Pasquale
Aug 30, 2008·The Journal of Biological Chemistry·Roberta NoberiniElena B Pasquale
Apr 6, 2013·Assay and Drug Development Technologies·Tom WehrmanBenjamin Bader
Jul 4, 2012·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Roberta NoberiniElena B Pasquale
Nov 3, 2011·Seminars in Cell & Developmental Biology·Roberta NoberiniElena B Pasquale
Nov 3, 2011·Seminars in Cell & Developmental Biology·Juha P Himanen
Aug 4, 2010·Biochemical and Biophysical Research Communications·Nikhil SinglaJuha P Himanen
Jun 25, 2014·Proceedings of the National Academy of Sciences of the United States of America·Amy K Y FuNancy Y Ip
Mar 10, 2010·Journal of Molecular Recognition : JMR·Robert J FalconerBrett M Collins
Jul 28, 2011·Chemical Biology & Drug Design·Roberta NoberiniElena B Pasquale
Apr 12, 2012·The Biochemical Journal·Ilaria LambertoElena B Pasquale
Jan 29, 2013·Chemistry & Biology·Bainan WuMaurizio Pellecchia
Nov 26, 2014·Proceedings of the National Academy of Sciences of the United States of America·Steven Setiawan ThengCaroline G Lee
Aug 21, 2013·Proceedings of the National Academy of Sciences of the United States of America·Kai XuDimitar B Nikolov
Sep 25, 2012·Bioorganicheskaia khimiia·S A Zozulya, I P Udovichenko
Apr 12, 2012·Journal of Biomolecular Screening·Claudiu M NelersaDaniel J Liebl
Apr 30, 2020·Expert Opinion on Investigational Drugs·Oscar J BuckensGodefridus J Peters
Apr 14, 2011·Natural Product Reports·Luis P CalleJesús Jiménez-Barbero
Nov 13, 2017·European Journal of Medicinal Chemistry·Aaron PettyBingcheng Wang
Oct 1, 2014·ACS Chemical Biology·Ilaria LambertoElena B Pasquale
Nov 5, 2021·Protein Science : a Publication of the Protein Society·Mei Dang, Jianxing Song

❮ Previous
Next ❯

Related Concepts

Related Feeds

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.