5JR2

Crystal structure of the EphA4 LBD in complex with APYd3 peptide inhibitor

Summary for 5JR2

• Entry DOI: 10.2210/pdb5jr2/pdb
• Descriptor: Ephrin type-A receptor 4, APYd3 peptide, HEXANE-1,6-DIOL, ... (5 entities in total)
• Functional Keywords: receptor tyrosine kinase, peptide inhibitor, ephrin, als, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 89020.84

Authors

Lechtenberg, B.C.,Olson, E.J.,Pasquale, E.B.,Dawson, P.E.,Riedl, S.J. (deposition date: 2016-05-05, release date: 2016-07-06, Last modification date: 2024-10-16)

Primary citation

Olson, E.J.,Lechtenberg, B.C.,Zhao, C.,Rubio de la Torre, E.,Lamberto, I.,Riedl, S.J.,Dawson, P.E.,Pasquale, E.B.
Modifications of a Nanomolar Cyclic Peptide Antagonist for the EphA4 Receptor To Achieve High Plasma Stability.
Acs Med.Chem.Lett., 7:841-846, 2016

PubMed Abstract: EphA4 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 (APYCVYRβASWSC-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 (βAPYCVYRβASWSC-nh2) and APY-d4 (βAPYCVYRβAEWEC-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.

PubMed: 27660688
DOI: 10.1021/acsmedchemlett.6b00132

Experimental method

X-RAY DIFFRACTION (1.75 Å)