More Like this

1. DOCKGROUND membrane protein-protein set

   https://doi.org/10.1371/journal.pone.0267531  

   Kotthoff, Ian ; Kundrotas, Petras J. ; Vakser, Ilya A. ( May 2022 , PLOS ONE)

   Soares, Claudio M. (Ed.)

   Membrane proteins are significantly underrepresented in Protein Data Bank despite their essential role in cellular mechanisms and the major progress in experimental protein structure determination. Thus, computational approaches are especially valuable in the case of membrane proteins and their assemblies. The main focus in developing structure prediction techniques has been on soluble proteins, in part due to much greater availability of the structural data. Currently, structure prediction of protein complexes (protein docking) is a well-developed field of study. However, the generic protein docking approaches are not optimal for the membrane proteins because of the differences in physicochemical environment and the spatial constraints imposed by the membranes. Thus, docking of the membrane proteins requires specialized computational methods. Development and benchmarking of the membrane protein docking approaches has to be based on high-quality sets of membrane protein complexes. In this study we present a new dataset of 456 non-redundant alpha helical binary interfaces. The set is significantly larger and more representative than the previously developed sets. In the future, it will become the basis for the development of docking and scoring benchmarks, similar to the ones for soluble proteins in the Dockground resource http://dockground.compbio.ku.edu . 

   more » « less
2. Elucidation of transient protein-protein interactions within carrier protein-dependent biosynthesis

   https://doi.org/10.1038/s42003-021-01838-3  

   Bartholow, Thomas G. ; Sztain, Terra ; Patel, Ashay ; Lee, D. John ; Young, Megan A. ; Abagyan, Ruben ; Burkart, Michael D. ( March 2021 , Communications Biology)

   Fatty acid biosynthesis (FAB) is an essential and highly conserved metabolic pathway. In bacteria, this process is mediated by an elaborate network of protein•protein interactions (PPIs) involving a small, dynamic acyl carrier protein that interacts with dozens of other partner proteins (PPs). These PPIs have remained poorly characterized due to their dynamic and transient nature. Using a combination of solution-phase NMR spectroscopy and protein-protein docking simulations, we report a comprehensive residue-by-residue comparison of the PPIs formed during FAB inEscherichia coli. This technique describes and compares the molecular basis of six discrete binding events responsible forE. coliFAB and offers insights into a method to characterize these events and those in related carrier protein-dependent pathways.

    

   more » « less
3. Computational Methods for Predicting Protein-Protein Interactions Using Various Protein Features

   https://doi.org/10.1002/cpps.62  

   Ding, Ziyun ; Kihara, Daisuke ( August 2018 , Current Protocols in Protein Science)
4. Inhibiting the Keap1/Nrf2 Protein‐Protein Interaction with Protein‐Like Polymers

   https://doi.org/10.1002/adma.202311467  

   Carrow, Kendal P. ; Hamilton, Haylee L. ; Hopps, Madeline P. ; Li, Yang ; Qiao, Baofu ; Payne, N. Connor ; Thompson, Matthew P. ; Zhang, Xiaoyu ; Magassa, Assa ; Fattah, Mara ; et al ( February 2024 , Advanced Materials)

   Successful and selective inhibition of the cytosolic protein‐protein interaction (PPI) between nuclear factor erythroid 2‐related factor 2 (Nrf2) and Kelch‐like ECH‐associating protein 1 (Keap1) can enhance the antioxidant response, with the potential for a therapeutic effect in a range of settings including in neurodegenerative disease (ND). Small molecule inhibitors have been developed, yet many have off‐target effects, or are otherwise limited by poor cellular permeability. Peptide‐based strategies have also been attempted to enhance specificity, yet face challenges due to susceptibility to degradation and lack of cellular penetration. Herein, these barriers are overcome utilizing a polymer‐based proteomimetics. The protein‐like polymer (PLP) consists of a synthetic, lipophilic polymer backbone displaying water soluble Keap1‐binding peptides on each monomer unit forming a brush polymer architecture. The PLPs are capable of engaging Keap1 and displacing the cellular protective transcription factor Nrf2, which then translocates to the nucleus, activating the antioxidant response element (ARE). PLPs exhibit increased Keap1 binding affinity by several orders of magnitude compared to free peptides, maintain serum stability, are cell‐penetrant, and selectively activate the ARE pathway in cells, including in primary cortical neuronal cultures. Keap1/Nrf2‐inhibitory PLPs have the potential to impact the treatment of disease states associated with dysregulation of oxidative stress, such as NDs.

    

   more » « less
5. Streamlined Protein‐Protein Interface Loop Mimicry

   https://doi.org/10.1002/ange.202307092  

   Mi, Tianxiong ; Siriwibool, Siriwalee ; Burgess, Kevin ( November 2023 , Angewandte Chemie)

   Cyclic peptides comprising endocyclic organic fragments,“cyclo‐organopeptides”, can be probes for perturbing protein‐protein interactions (PPIs). Finding loop mimics is difficult because of high conformational variability amongst targets. Backbone Matching (BM), introduced here, helps solve this problem in the illustrative cases by facilitating efficient evaluation of virtualcyclo‐organopeptide core‐structure libraries. Thus, 86 rigid organic fragments were selected to build a library of 602cyclo‐organopeptides comprising Ala and organic parts:“cyclo‐{‐(Ala)_n‐organo‐}”. The central hypothesis is “hit” library members have accessible low energy conformers corresponding to backbone structures of target protein loops, while library members whichcannotattain this conformation are probably unworthy of further evaluation. BM thereby prioritizes candidate loop mimics, so that less than 10 cyclo‐organopeptides are needed to be prepared to find leads for two illustrative PPIs: iNOS ⋅ SPSB2, and uPA ⋅ uPAR.

    

   more » « less