Rigidified Clicked Dimeric Ligands for Studying the Dynamics of the PDZ1-2 Supramodule of PSD-95

Jonas N N Eildal; Anders Bach; Jakob Dogan; Fei Ye; Mingjie Zhang; Per Jemth; Kristian Strømgaard

doi:10.1002/cbic.201402547

Rigidified Clicked Dimeric Ligands for Studying the Dynamics of the PDZ1-2 Supramodule of PSD-95

Jonas N N Eildal, Anders Bach, Jakob Dogan, Fei Ye, Mingjie Zhang, Per Jemth, Kristian Strømgaard

11 Citationer (Scopus)

Abstract

PSD-95 is a scaffolding protein of the MAGUK protein family, and engages in several vital protein-protein interactions in the brain with its PDZ domains. It has been suggested that PSD-95 is composed of two supramodules, one of which is the PDZ1-2 tandem domain. Here we have developed rigidified high-affinity dimeric ligands that target the PDZ1-2 supramodule, and established the biophysical parameters of the dynamic PDZ1-2/ligand interactions. By employing ITC, protein NMR, and stopped-flow kinetics this study provides a detailed insight into the overall conformational energetics of the interaction between dimeric ligands and tandem PDZ domains. Our findings expand our understanding of the dynamics of PSD-95 with potential relevance to its biological role in interacting with multivalent receptor complexes and development of novel drugs.

Originalsprog	Engelsk
Tidsskrift	ChemBioChem
Vol/bind	16
Sider (fra-til)	64–69
Antal sider	6
ISSN	1439-4227
DOI	https://doi.org/10.1002/cbic.201402547
Status	Udgivet - 2 jan. 2015

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10.1002/cbic.201402547

Citationsformater

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abstract = "PSD-95 is a scaffolding protein of the MAGUK protein family, and engages in several vital protein-protein interactions in the brain with its PDZ domains. It has been suggested that PSD-95 is composed of two supramodules, one of which is the PDZ1-2 tandem domain. Here we have developed rigidified high-affinity dimeric ligands that target the PDZ1-2 supramodule, and established the biophysical parameters of the dynamic PDZ1-2/ligand interactions. By employing ITC, protein NMR, and stopped-flow kinetics this study provides a detailed insight into the overall conformational energetics of the interaction between dimeric ligands and tandem PDZ domains. Our findings expand our understanding of the dynamics of PSD-95 with potential relevance to its biological role in interacting with multivalent receptor complexes and development of novel drugs.",

author = "Eildal, {Jonas N N} and Anders Bach and Jakob Dogan and Fei Ye and Mingjie Zhang and Per Jemth and Kristian Str{\o}mgaard",

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T1 - Rigidified Clicked Dimeric Ligands for Studying the Dynamics of the PDZ1-2 Supramodule of PSD-95

AU - Eildal, Jonas N N

AU - Bach, Anders

AU - Dogan, Jakob

AU - Ye, Fei

AU - Zhang, Mingjie

AU - Jemth, Per

AU - Strømgaard, Kristian

PY - 2015/1/2

Y1 - 2015/1/2

N2 - PSD-95 is a scaffolding protein of the MAGUK protein family, and engages in several vital protein-protein interactions in the brain with its PDZ domains. It has been suggested that PSD-95 is composed of two supramodules, one of which is the PDZ1-2 tandem domain. Here we have developed rigidified high-affinity dimeric ligands that target the PDZ1-2 supramodule, and established the biophysical parameters of the dynamic PDZ1-2/ligand interactions. By employing ITC, protein NMR, and stopped-flow kinetics this study provides a detailed insight into the overall conformational energetics of the interaction between dimeric ligands and tandem PDZ domains. Our findings expand our understanding of the dynamics of PSD-95 with potential relevance to its biological role in interacting with multivalent receptor complexes and development of novel drugs.

AB - PSD-95 is a scaffolding protein of the MAGUK protein family, and engages in several vital protein-protein interactions in the brain with its PDZ domains. It has been suggested that PSD-95 is composed of two supramodules, one of which is the PDZ1-2 tandem domain. Here we have developed rigidified high-affinity dimeric ligands that target the PDZ1-2 supramodule, and established the biophysical parameters of the dynamic PDZ1-2/ligand interactions. By employing ITC, protein NMR, and stopped-flow kinetics this study provides a detailed insight into the overall conformational energetics of the interaction between dimeric ligands and tandem PDZ domains. Our findings expand our understanding of the dynamics of PSD-95 with potential relevance to its biological role in interacting with multivalent receptor complexes and development of novel drugs.

U2 - 10.1002/cbic.201402547

DO - 10.1002/cbic.201402547

M3 - Journal article

C2 - 25407949

SN - 1439-4227

VL - 16

SP - 64

EP - 69

JO - ChemBioChem

JF - ChemBioChem

ER -

Rigidified Clicked Dimeric Ligands for Studying the Dynamics of the PDZ1-2 Supramodule of PSD-95

Abstract

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