Structural highlights
4ra0 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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| Method: | X-ray diffraction, Resolution 3.07Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
GAS6_HUMAN Ligand for tyrosine-protein kinase receptors AXL, TYRO3 and MER whose signaling is implicated in cell growth and survival, cell adhesion and cell migration. GAS6/AXL signaling plays a role in various processes such as endothelial cell survival during acidification by preventing apoptosis, optimal cytokine signaling during human natural killer cell development, hepatic regeneration, gonadotropin-releasing hormone neuron survival and migration, platelet activation, or regulation of thrombotic responses.[1] [2]
Publication Abstract from PubMed
Aberrant signaling through the Axl receptor tyrosine kinase has been associated with a myriad of human diseases, most notably metastatic cancer, identifying Axl and its ligand Gas6 as important therapeutic targets. Using rational and combinatorial approaches, we engineered an Axl 'decoy receptor' that binds Gas6 with high affinity and inhibits its function, offering an alternative approach from drug discovery efforts that directly target Axl. Four mutations within this high-affinity Axl variant caused structural alterations in side chains across the Gas6-Axl binding interface, stabilizing a conformational change on Gas6. When reformatted as an Fc fusion, the engineered decoy receptor bound Gas6 with femtomolar affinity, an 80-fold improvement compared to binding of the wild-type Axl receptor, allowing effective sequestration of Gas6 and specific abrogation of Axl signaling. Moreover, increased Gas6 binding affinity was critical and correlative with the ability of decoy receptors to potently inhibit metastasis and disease progression in vivo.
An engineered Axl 'decoy receptor' effectively silences the Gas6-Axl signaling axis.,Kariolis MS, Miao YR, Jones DS 2nd, Kapur S, Mathews II, Giaccia AJ, Cochran JR Nat Chem Biol. 2014 Nov;10(11):977-83. doi: 10.1038/nchembio.1636. Epub 2014 Sep , 21. PMID:25242553[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ D'Arcangelo D, Gaetano C, Capogrossi MC. Acidification prevents endothelial cell apoptosis by Axl activation. Circ Res. 2002 Oct 4;91(7):e4-12. PMID:12364394
- ↑ Park IK, Giovenzana C, Hughes TL, Yu J, Trotta R, Caligiuri MA. The Axl/Gas6 pathway is required for optimal cytokine signaling during human natural killer cell development. Blood. 2009 Mar 12;113(11):2470-7. doi: 10.1182/blood-2008-05-157073. Epub 2008, Oct 7. PMID:18840707 doi:10.1182/blood-2008-05-157073
- ↑ Kariolis MS, Miao YR, Jones DS 2nd, Kapur S, Mathews II, Giaccia AJ, Cochran JR. An engineered Axl 'decoy receptor' effectively silences the Gas6-Axl signaling axis. Nat Chem Biol. 2014 Nov;10(11):977-83. doi: 10.1038/nchembio.1636. Epub 2014 Sep , 21. PMID:25242553 doi:http://dx.doi.org/10.1038/nchembio.1636
