5NZ9

NMR structure of an EphA2-Sam fragment

Summary for 5NZ9

• Entry DOI: 10.2210/pdb5nz9/pdb
• NMR Information: BMRB: 34138
• Descriptor: Ephrin type-A receptor 2 (1 entity in total)
• Functional Keywords: ephrin receptor, sam domain, tfe nmr, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 2877.48

Authors

Mercurio, F.A.,Leone, M. (deposition date: 2017-05-12, release date: 2017-12-20, Last modification date: 2024-11-20)

Primary citation

Mercurio, F.A.,Di Natale, C.,Pirone, L.,Iannitti, R.,Marasco, D.,Pedone, E.M.,Palumbo, R.,Leone, M.
The Sam-Sam interaction between Ship2 and the EphA2 receptor: design and analysis of peptide inhibitors.
Sci Rep, 7:17474-17474, 2017

PubMed Abstract: The lipid phosphatase Ship2 represents a drug discovery target for the treatment of different diseases, including cancer. Its C-terminal sterile alpha motif domain (Ship2-Sam) associates with the Sam domain from the EphA2 receptor (EphA2-Sam). This interaction is expected to mainly induce pro-oncogenic effects in cells therefore, inhibition of the Ship2-Sam/EphA2-Sam complex may represent an innovative route to discover anti-cancer therapeutics. In the present work, we designed and analyzed several peptide sequences encompassing the interaction interface of EphA2-Sam for Ship2-Sam. Peptide conformational analyses and interaction assays with Ship2-Sam conducted through diverse techniques (CD, NMR, SPR and MST), identified a positively charged penta-amino acid native motif in EphA2-Sam, that once repeated three times in tandem, binds Ship2-Sam. NMR experiments show that the peptide targets the negatively charged binding site of Ship2-Sam for EphA2-Sam. Preliminary in vitro cell-based assays indicate that -at 50 µM concentration- it induces necrosis of PC-3 prostate cancer cells with more cytotoxic effect on cancer cells than on normal dermal fibroblasts. This work represents a pioneering study that opens further opportunities for the development of inhibitors of the Ship2-Sam/EphA2-Sam complex for therapeutic applications.

PubMed: 29234063
DOI: 10.1038/s41598-017-17684-5

Experimental method

SOLUTION NMR