5jr2 | pdb_00005jr2
Crystal structure of the EphA4 LBD in complex with APYd3 peptide inhibitor
Structural highlights
FunctionEPHA4_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.[1] Publication Abstract from PubMedEphA4 is a receptor tyrosine kinase with a critical role in repulsive axon guidance and synaptic function. However, aberrant EphA4 activity can inhibit neural repair after injury and exacerbate neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's. We previously identified the cyclic peptide APY-d2 (APYCVYRbetaASWSC-nh2, containing a disulfide bond) as a potent and selective EphA4 antagonist. However, APY-d2 lacks sufficient plasma stability to be useful for EphA4 inhibition in vivo through peripheral administration. Using structure-activity relationship studies, we show that protecting the peptide N-terminus from proteolytic degradation dramatically increases the persistence of the active peptide in plasma and that a positively charged peptide N-terminus is essential for high EphA4 binding affinity. Among several improved APY-d2 derivatives, the cyclic peptides APY-d3 (betaAPYCVYRbetaASWSC-nh2) and APY-d4 (betaAPYCVYRbetaAEWEC-nh2) combine high stability in plasma and cerebrospinal fluid with slightly enhanced potency. These properties make them valuable research tools and leads toward development of therapeutics for neurological diseases. Modifications of a Nanomolar Cyclic Peptide Antagonist for the EphA4 Receptor To Achieve High Plasma Stability.,Olson EJ, Lechtenberg BC, Zhao C, Rubio de la Torre E, Lamberto I, Riedl SJ, Dawson PE, Pasquale EB ACS Med Chem Lett. 2016 Jun 25;7(9):841-6. doi: 10.1021/acsmedchemlett.6b00132., eCollection 2016 Sep 8. PMID:27660688[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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