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Semirational design of Jun-Fos coiled coils with increased affinity: Universal implications for
 

Summary: Semirational design of Jun-Fos coiled coils with
increased affinity: Universal implications for
leucine zipper prediction and design
Jody M. Mason, Mark A. Schmitz, Kristian M. Mu¨ ller, and Katja M. Arndt*
Institut fu¨ r Biologie III, Universita¨t Freiburg, Scha¨nzlestrasse 1, D-79104 Freiburg, Germany
Edited by Jennifer A. Doudna, University of California, Berkeley, CA, and approved April 18, 2006 (received for review November 14, 2005)
Activator protein-1 (AP-1) is a crucial transcription factor implicated
in numerous cancers. For this reason, nine homologues of the AP-1
leucine zipper region have been characterized: Fos (c-Fos, FosB,
Fra1, and Fra2), Jun (c-Jun, JunB, and JunD), and semirational
library-designed winning peptides FosW and JunW. The latter two
were designed to specifically target c-Fos or c-Jun. They have been
identified by using protein-fragment complementation assays
combined with growth competition. This assay removes nonspe-
cific, unstable, and protease susceptible library members from the
pool, leaving winners with excellent drug potential. Thermal melts
of all 45 possible dimeric interactions have been surveyed, with the
FosW­c-Jun complex displaying a melting temperature (Tm) of
63°C, compared to only 16°C for wild-type c-Fos­c-Jun interaction.
This impressive 70,000-fold KD decrease is largely due to optimized

  

Source: Arndt, Katja - Institut für Biologie III, Albert-Ludwigs-Universität Freiburg
Müller, Kristian - Institut für Biologie III, Albert-Ludwigs-Universität Freiburg

 

Collections: Biology and Medicine; Biotechnology