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The role of modulator residues in PDZ domain binding interactions
Author(s) -
Amacher Jeanine,
Cushing Patrick R,
Brooks Lionel,
Boisguerin Prisca,
Madden Dean R
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.559.6
Subject(s) - pdz domain , binding selectivity , chemistry , peptide , computational biology , affinities , binding site , plasma protein binding , gene isoform , drug discovery , biochemistry , biophysics , biology , gene
PDZ domains are the most common interaction domain in the human proteome. PDZ interactions are classified by motif residues, or, preferences distinguished by high throughput techniques. However, these motifs are degenerate, and fail to predict the affinities of each peptide‐binding domain for its unique set of interacting partners, making design of specific therapeutic inhibitors a challenge. Through biochemical, structural, and computational studies, we reveal that targeted inhibitor design requires an understanding of modulatory, or non‐motif affinity determinant, residues in PDZ domains. Our work investigates modulatory preferences in the CFTR Associated Ligand (CAL) protein. Despite a motif dependent on two residues, we previously reported the engineering of a selective inhibitor of CAL PDZ via a peptide array pipeline. Our approach allowed us to identify multiple residues along the binding cleft that influenced affinity and/or selectivity. We now investigate the stereochemistry and binding affinities of over a dozen co‐complex structures of CAL PDZ bound to high, intermediate, and low affinity peptides, revealing distinct modulator preferences that are hidden from high throughput motif analysis. We extend our analysis to additional PDZ domains, which share cellular targets. Our data suggests that modulator preferences dictate endogenous PDZ networks.