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Probing backbone hydrogen bonding in PDZ/ligand interactions by protein amide-to-ester mutations
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2014 (English)In: Nature Communications, ISSN 2041-1723, Vol. 5, 3215- p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2014. Vol. 5, 3215- p.
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Medical and Health Sciences
URN: urn:nbn:se:uu:diva-220317DOI: 10.1038/ncomms4215ISI: 000331126500001OAI: diva2:705452
Available from: 2014-03-17 Created: 2014-03-12 Last updated: 2014-09-18Bibliographically approved

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Hultqvist, GretaJemth, Per
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