scholarly journals Theoretical models of inhibitory activity for inhibitors of protein–protein interactions: targeting menin–mixed lineage leukemia with small molecules

MedChemComm ◽  
2017 ◽  
Vol 8 (12) ◽  
pp. 2216-2227 ◽  
Author(s):  
Wiktoria Jedwabny ◽  
Szymon Kłossowski ◽  
Trupta Purohit ◽  
Tomasz Cierpicki ◽  
Jolanta Grembecka ◽  
...  
Keyword(s):  
Small Molecules ◽  
Binding Affinity ◽  
Protein Interactions ◽  
Empirical Model ◽  
Inhibitory Activity ◽  
Theoretical Models ◽  
Mixed Lineage Leukemia ◽  
Protein Protein Interactions ◽  
Model Based ◽  
Dispersion Terms

A computationally affordable, non-empirical model based on electrostatic multipole and dispersion terms successfully predicts the binding affinity of inhibitors of menin–MLL protein–protein interactions.

scholarly journals Engineered pH-Sensitive Protein G / IgG Interaction

2020 ◽  
Author(s):  
Ramesh K. Jha ◽  
Allison Yankey ◽  
Kalifa Shabazz ◽  
Leslie Naranjo ◽  
Nileena Velappan ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Protein Design ◽  
Protein Interactions ◽  
Rational Design ◽  
Protein G ◽  
Acidic Ph ◽  
Protein Protein Interactions ◽  
Natural Interface ◽  
Complex Stimuli ◽  
Igg Purification

ABSTRACTWhile natural protein-protein interactions have evolved to be induced by complex stimuli, rational design of interactions that can be switched-on-demand still remain challenging in the protein design world. Here, we demonstrate a computationally redesigned natural interface for improved binding affinity could further be mutated to adopt a pH switchable interaction. The redesigned interface of Protein G-IgG Fc domain, when incorporated with histidine and glutamic acid on Protein G (PrG-EHHE), showed a switch in binding affinity by 50-fold when pH was altered from mild acidic to mild basic. The wild type (WT) interface only showed negligible switch. The overall binding affinity at mild acidic pH for PrG-EHHE outperformed the WT PrG interaction. The new reagent PrG-EHHE will be revolutionary in IgG purification since the traditional method of using an extreme acidic pH for elution can be circumvented.Abstract Figure

Small Molecules Targeting Protein–Protein Interactions: A Promising Anti-HIV Strategy

2010 ◽  
Vol 86 (1) ◽  
pp. A32
Author(s):  
Alba Chimirri ◽  
Laura De Luca ◽  
Stefania Ferro ◽  
Rosaria Gitto ◽  
Anna Maria Monforte ◽  
...  
Keyword(s):  
Small Molecules ◽  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Anti Hiv

scholarly journals Modulating Protein–Protein Interactions with Small Molecules: The Importance of Binding Hotspots

2012 ◽  
Vol 415 (2) ◽  
pp. 443-453 ◽  
Author(s):  
Ratna Rajesh Thangudu ◽  
Stephen H. Bryant ◽  
Anna R. Panchenko ◽  
Thomas Madej
Keyword(s):  
Small Molecules ◽  
Protein Interactions ◽  
Protein Protein Interactions

scholarly journals Cost function network-based design of protein–protein interactions: predicting changes in binding affinity

2018 ◽  
Vol 34 (15) ◽  
pp. 2581-2589 ◽  
Author(s):  
Clément Viricel ◽  
Simon de Givry ◽  
Thomas Schiex ◽  
Sophie Barbe
Keyword(s):  
Cost Function ◽  
Binding Affinity ◽  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Function Network

scholarly journals Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
James O’Connell ◽  
John Porter ◽  
Boris Kroeplien ◽  
Tim Norman ◽  
Stephen Rapecki ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Protein Interactions ◽  
General Mechanism ◽  
Protein Protein Interactions ◽  
Biologic Drugs ◽  
Small Molecule Drugs ◽  
Necrosis Factor

AbstractTumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn’s disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein–protein interactions.

scholarly journals Engineering an improved light-induced dimer (iLID) for controlling the localization and activity of signaling proteins

2014 ◽  
Vol 112 (1) ◽  
pp. 112-117 ◽  
Author(s):  
Gurkan Guntas ◽  
Ryan A. Hallett ◽  
Seth P. Zimmerman ◽  
Tishan Williams ◽  
Hayretin Yumerefendi ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Protein Design ◽  
Protein Interactions ◽  
Mammalian Cell Culture ◽  
Large Change ◽  
Small Gtpase ◽  
Protein Protein Interactions ◽  
Binding Assays ◽  
Light Stimulation ◽  
Inducible Protein

The discovery of light-inducible protein–protein interactions has allowed for the spatial and temporal control of a variety of biological processes. To be effective, a photodimerizer should have several characteristics: it should show a large change in binding affinity upon light stimulation, it should not cross-react with other molecules in the cell, and it should be easily used in a variety of organisms to recruit proteins of interest to each other. To create a switch that meets these criteria we have embedded the bacterial SsrA peptide in the C-terminal helix of a naturally occurring photoswitch, the light-oxygen-voltage 2 (LOV2) domain from Avena sativa. In the dark the SsrA peptide is sterically blocked from binding its natural binding partner, SspB. When activated with blue light, the C-terminal helix of the LOV2 domain undocks from the protein, allowing the SsrA peptide to bind SspB. Without optimization, the switch exhibited a twofold change in binding affinity for SspB with light stimulation. Here, we describe the use of computational protein design, phage display, and high-throughput binding assays to create an improved light inducible dimer (iLID) that changes its affinity for SspB by over 50-fold with light stimulation. A crystal structure of iLID shows a critical interaction between the surface of the LOV2 domain and a phenylalanine engineered to more tightly pin the SsrA peptide against the LOV2 domain in the dark. We demonstrate the functional utility of the switch through light-mediated subcellular localization in mammalian cell culture and reversible control of small GTPase signaling.

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