Probing backbone hydrogen bonding in PDZ/ligand interactions by protein amide-to-ester mutations

Søren W. Pedersen, Stine B. Pedersen, Louise Anker, Greta Hultqvist, Anders S. Kristensen, Per Jemth and Kristian Strømgaard ()
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Søren W. Pedersen: University of Copenhagen
Stine B. Pedersen: University of Copenhagen
Louise Anker: University of Copenhagen
Greta Hultqvist: Uppsala University
Anders S. Kristensen: University of Copenhagen
Per Jemth: Uppsala University
Kristian Strømgaard: University of Copenhagen

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: Abstract PDZ domains are scaffolding modules in protein–protein interactions that mediate numerous physiological functions by interacting canonically with the C-terminus or non-canonically with an internal motif of protein ligands. A conserved carboxylate-binding site in the PDZ domain facilitates binding via backbone hydrogen bonds; however, little is known about the role of these hydrogen bonds due to experimental challenges with backbone mutations. Here we address this interaction by generating semisynthetic PDZ domains containing backbone amide-to-ester mutations and evaluating the importance of individual hydrogen bonds for ligand binding. We observe substantial and differential effects upon amide-to-ester mutation in PDZ2 of postsynaptic density protein 95 and other PDZ domains, suggesting that hydrogen bonding at the carboxylate-binding site contributes to both affinity and selectivity. In particular, the hydrogen-bonding pattern is surprisingly different between the non-canonical and canonical interaction. Our data provide a detailed understanding of the role of hydrogen bonds in protein–protein interactions.

Date: 2014
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DOI: 10.1038/ncomms4215

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