A Novel Determinant of PSMD9 PDZ Binding Guides the Evolution of the First Generation of Super Binding Peptides

A Novel Determinant of PSMD9 PDZ Binding Guides the Evolution of the First Generation of Super Binding Peptides
Title:
A Novel Determinant of PSMD9 PDZ Binding Guides the Evolution of the First Generation of Super Binding Peptides
Other Titles:
Biochemistry
Publication Date:
09 July 2019
Citation:
Biochemistry 2019, 58, 32, 3422-3433
Abstract:
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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Funding Info:
This project was funded by Department of Biotechnology (DBT), Government of India (BT/PR21237/BRB/10/1550/2016) and Intramural Grant, ACTREC (Project No. 258). M.H. acknowledges ACTREC (and Intramural grant (Project No. 258)) for fellowship.
Description:
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Biochemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.biochem.9b00308
ISSN:
0006-2960
1520-4995
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