A high‐affinity, bivalent
            <scp>PDZ</scp>
            domain inhibitor complexes
            <scp>PICK</scp>
            1 to alleviate neuropathic pain

Christensen, Nikolaj Riis; Luca, Marta De; Lever, Michael B; Richner, Mette; Hansen, Astrid B; Noes-Holt, Gith; Jensen, Kathrine L.; Rathje, Mette; Jensen, Dennis Bo; Erlendsson, Simon; Bartling, Christian R. O.; Ammendrup-Johnsen, Ina; Pedersen, Sofie; Schönauer, Michèle; Nissen, Klaus B.; Midtgaard, Søren Roi; Teilum, Kaare; Sørensen, Andreas T.; Bach, Anders; Strømgaard, Kristian; Meehan, Claire Francesca; Vægter, Christian Bjerggaard; Gether, Ulrik; Madsen, Kenneth L.

doi:10.15252/emmm.201911248

Cited by 23 publications

(54 citation statements)

References 94 publications

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“…In good agreement with theory we showed that the retention time and equilibration time becomes extremely long (t 1/2 , ~ 375 min, k on,av ~ 25 min at a concentration of 5 times K av ) (Erlendsson et al, 2019 ). From this insight, a high avidity bivalent inhibitor of PICK has recently been developed that alleviate neuropathic pain in rats (Christensen et al, 2020 ).…”

Section: Intracellular Aviditymentioning

confidence: 99%

“…In addition to the effects we have described in this review, multivalency may also lead to a series of other properties not observed for monovalent protein-ligand complexes. Designing multivalent drugs have huge potential and is already widely applied (Mourez et al, 2001 ; Kim et al, 2008 ; Bach et al, 2012 ; Dubacheva et al, 2015 ; Karlsson et al, 2015 ; Maric et al, 2015 ; Einav et al, 2019 ; Christensen et al, 2020 ; Ortega et al, 2020 ). Within the past 5 years it has become increasingly clear how multivalent interactions of particularly RNA and IDP's drive liquid-liquid phase separations (Cohan and Pappu, 2020 ; Conicella et al, 2020 ; Guillén-Boixet et al, 2020 ; Martin et al, 2020 ; Ryan et al, 2020 ).…”

Section: Emerging Concepts and Future Perspectivesmentioning

confidence: 99%

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Binding Revisited—Avidity in Cellular Function and Signaling

Erlendsson

Teilum

2021

Front. Mol. Biosci.

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When characterizing biomolecular interactions, avidity, is an umbrella term used to describe the accumulated strength of multiple specific and unspecific interactions between two or more interaction partners. In contrast to the affinity, which is often sufficient to describe monovalent interactions in solution and where the binding strength can be accurately determined by considering only the relationship between the microscopic association and dissociation rates, the avidity is a phenomenological macroscopic parameter linked to several microscopic events. Avidity also covers potential effects of reduced dimensionality and/or hindered diffusion observed at or near surfaces e.g., at the cell membrane. Avidity is often used to describe the discrepancy or the “extra on top” when cellular interactions display binding that are several orders of magnitude stronger than those estimated in vitro. Here we review the principles and theoretical frameworks governing avidity in biological systems and the methods for predicting and simulating avidity. While the avidity and effects thereof are well-understood for extracellular biomolecular interactions, we present here examples of, and discuss how, avidity and the underlying kinetics influences intracellular signaling processes.

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Section: Intracellular Aviditymentioning

confidence: 99%

Section: Emerging Concepts and Future Perspectivesmentioning

confidence: 99%

Binding Revisited—Avidity in Cellular Function and Signaling

Erlendsson

Teilum

2021

Front. Mol. Biosci.

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“…A recent work reports a small molecule inhibitor, Tat-P 4 -(C5) 2 , with both strong affinity and specificity to the PICK1 PDZ domain. 30 Furthermore, Tat-P 4 -(C5) 2 demonstrates efficacy in reducing addiction-like behavior in mice. 75 Tat-P 4 -(C5) 2 interacts with the binding pocket of the PDZ domain as well as negatively charged residues on of β B- β C loop which introduces an additional layer of stabilization.…”

Section: Discussionmentioning

confidence: 99%

“…26–29 A recent work by Christensen et al shed light on a drug which can partially reduce the biological function of PICK1. 30 In parallel, computational groups have aided this effort by performing molecular dynamics (MD) simulations to reveal intradomain interactions of other PDZ domains and PDZ-ligand interactions. 29,31–44 Furthermore, some efforts have been put towards understanding the structural and energetic allosterism of PDZ domains overall.…”

Section: Introductionmentioning

confidence: 99%

The electrostatic allostery could be the trigger for the changes in dynamics for the PDZ domain of PICK1

Stevens¹,

He²

2020

Preprint

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The PDZ domain is a highly abundant protein-protein interaction domain that exists in many signaling proteins, such as PICK1. Despite the highly conserved structure of the PDZ family, the PDZ family has an extremely low sequence identity, making each PDZ domain unique. PICK1 is the only protein in the human genome that is comprised of a PDZ domain and a BAR domain. PICK1 regulates surface membrane proteins and has been identified as an integral player in drug addiction. Like many PDZ-containing proteins, PICK1 is positively regulated by its PDZ domain and has thus drawn attention to be a potential drug target to curb the effects of substance abuse. The goal of this study is to use all-atom molecular dynamics simulations and the electrostatic analysis program, DelPhi, to better understand the unique interactions and dynamic changes in the PICK1 PDZ domain upon complex formation. Our results demonstrated that the PICK1 PDZ domain shares similar canonical PDZ-ligand hydrogen bonding networks and fluctuations of the carboxylate-binding loop to other PDZ domains. Furthermore, our results are unique to the PICK1 PDZ domain as we reveal that the binding of ligand opens up the binding pocket and, at the same time, reduces the fluctuations of both the central part of the binding pocket and the short loop region between the αA-helix and βC-strand. More importantly, the binding of ligand resulted in charge redistribution at the binding pocket region as well as the N- and C-termini of the PDZ domain that are not a part of the binding pocket. These results suggest that the electrostatic allostery resulted from ligand binding could be the key factor leading to the changes in dynamics which may be associated with the activation of PICK1. Based on these results, an effective drug to target PDZ domain must not only stably bind to the PICK1 PDZ domain but also prevent the electrostatic allostery of the PDZ domain.

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“…A significant fraction of PPIs is dependent on short linear peptides, which are increasingly recognized for their roles in signaling and regulatory networks ( Pawson and Nash, 2003 ) and antibody/antigen recognition ( Brennan et al., 2010 ). Thus, they provide opportunities for therapeutic intervention and valuable starting points for the development of immunological biopharmaceuticals ( Fosgerau and Hoffmann, 2015 ) and the design of PPI modulators ( Christensen et al., 2020 ). Widely applied methods for the characterization and affinity determination of PPIs include peptide and protein microarrays ( Lyamichev et al., 2017 ; Templin et al., 2002 ), surface plasmon resonance (SPR) ( Patching, 2014 ), biolayer interferometry (BLI) ( Sultana and Lee, 2015 ), isothermal calorimetry (ITC) ( Ye and Wu, 2000 ), fluorescence polarization (FP) ( Rooklin et al., 2017 ), and microscale thermophoresis (MST) ( Duhr and Braun, 2006 ; Wienken et al., 2010 ).…”

Section: Introductionmentioning

confidence: 99%

High-throughput determination of protein affinities using unmodified peptide libraries in nanomolar scale

et al. 2021

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Summary Protein-protein interactions (PPIs) are of fundamental importance for our understanding of physiology and pathology. PPIs involving short, linear motifs play a major role in immunological recognition, signaling, and regulation and provide attractive starting points for pharmaceutical intervention. Yet, state-of-the-art protein-peptide affinity determination approaches exhibit limited throughput and sensitivity, often resulting from ligand immobilization, labeling, or synthesis. Here, we introduce a high-throughput method for in-solution analysis of protein-peptide interactions using a phenomenon called temperature related intensity change (TRIC). We use TRIC for the identification and fine-mapping of low- and high-affinity protein interaction sites and the definition of sequence binding requirements. Validation is achieved by microarray-based studies using wild-type and mutated recombinant protein and the native protein within tissue lysates. On-chip neutralization and strong correlation with structural data establish TRIC as a quasi-label-free method to determine binding affinities of unmodified peptide libraries with large dynamic range.

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A high‐affinity, bivalent PDZ domain inhibitor complexes PICK 1 to alleviate neuropathic pain

Cited by 23 publications

References 94 publications

Binding Revisited—Avidity in Cellular Function and Signaling

Binding Revisited—Avidity in Cellular Function and Signaling

The electrostatic allostery could be the trigger for the changes in dynamics for the PDZ domain of PICK1

High-throughput determination of protein affinities using unmodified peptide libraries in nanomolar scale

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