The
PDZ domain is one of the most widespread protein interaction
domains found in nature. Due to their integral role in numerous biological
functions, their ability to act as scaffolds for signal amplification,
and the occurrence of mutations linked to human diseases, PDZ domains
are attractive therapeutic targets. On the basis of the differential
binding affinities of selected C-terminal peptides of the human proteome
for one such PDZ domain (PSMD9) and by exploring structure–activity
relationships, we design and convert a low-affinity tetrapeptide (∼439
μM) to a tight binding sequence (∼5 μM). The peptide
inhibits PSMD9–hnRNPA1 interactions that are critical in basal
and stimulus-induced NF-κB signaling and a potential therapeutic
target in cancers, including chemotherapy or radiation-induced therapy
resistance. Extensive application of computer modeling, including
ligand mapping and all-atom molecular dynamics simulations, helps
us to rationalize the structural basis for the huge differences in
binding affinity and inform us about the residue-wise contributions
to the binding energy. Our findings are in accord with the classical
preference of the (PSMD9) PDZ domain for C-terminal sequences that
contain hydrophobic residues at the P0 (C-terminal) position. In addition,
for the first time, we identify a hitherto unknown occupancy for cysteine
at the P–2 position that drives high-affinity interaction in
a PDZ domain.
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