Combating drug resistance in Chronic Myeloid Leukemia and HIV-1 infection. Structural insights into the hypusine modification of eIF-5A Protein. (Poster)

SEBASTIÁN KLINKE; SASCHA KRETSCHMANN; CHRIS MEIER; JOACHIM HAUBER; ROLF HILGENFELD

Kiel

Simposio; 2nd Annual Symposium of the Cluster of Excellence “Inflammation at Interfaces”; 2009

Cluster of Excellence “Inflammation at Interfaces”

Hypusine is a basic amino acid that occurs in a single protein, the eukaryotic translation initiationfactor 5A (eIF-5A). It is formed by two consecutive post-translational reactions on a particular lysine residue, which are catalyzed by deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH). Hypusinecontaining eIF-5A is essential for eukaryotic cell proliferation. It is known that this protein is involved in the Rev-mediated mRNA nuclear export in HIV-1 infection, and that its expression is down-regulated in Chronic Myelogenous Leukemia. Targeting this unique post-translational modification by inhibition of the DHS catalytic activity presents a key advantage in comparison to classical antiviral treatments, in that no drug resistance can be developed since the target is a host protein. To date, the Phase-II drug CNI-1493 (semapimod) has been shown to be a potent inhibitor of the human DHS. As part of this project, we aim to determine the crystallographic structure of DHS with bound CNI-1493 and also to understand the nature of hypusine formation by studying the structure of the complex between DHS and eIF-5A.