Computational Design of PDZ-Peptide Binding

2021 ◽  
pp. 237-255
Author(s):  
Nicolas Panel ◽  
Francesco Villa ◽  
Vaitea Opuu ◽  
David Mignon ◽  
Thomas Simonson
Keyword(s):  
Peptide Binding ◽  
Computational Design

scholarly journals Peptide design by optimization on a data-parameterized protein interaction landscape

2018 ◽  
Vol 115 (44) ◽  
pp. E10342-E10351 ◽  
Author(s):  
Justin M. Jenson ◽  
Vincent Xue ◽  
Lindsey Stretz ◽  
Tirtha Mandal ◽  
Lothar “Luther” Reich ◽  
...  
Keyword(s):  
Dimensional Space ◽  
Peptide Binding ◽  
Cancer Therapeutics ◽  
Computational Design ◽  
Diagnostic Tools ◽  
Binding Affinities ◽  
Design Problems ◽  
Multiple Protein ◽  
Helical Peptide ◽  
Protein Properties

Many applications in protein engineering require optimizing multiple protein properties simultaneously, such as binding one target but not others or binding a target while maintaining stability. Such multistate design problems require navigating a high-dimensional space to find proteins with desired characteristics. A model that relates protein sequence to functional attributes can guide design to solutions that would be hard to discover via screening. In this work, we measured thousands of protein–peptide binding affinities with the high-throughput interaction assay amped SORTCERY and used the data to parameterize a model of the alpha-helical peptide-binding landscape for three members of the Bcl-2 family of proteins: Bcl-xL, Mcl-1, and Bfl-1. We applied optimization protocols to explore extremes in this landscape to discover peptides with desired interaction profiles. Computational design generated 36 peptides, all of which bound with high affinity and specificity to just one of Bcl-xL, Mcl-1, or Bfl-1, as intended. We designed additional peptides that bound selectively to two out of three of these proteins. The designed peptides were dissimilar to known Bcl-2–binding peptides, and high-resolution crystal structures confirmed that they engaged their targets as expected. Excellent results on this challenging problem demonstrate the power of a landscape modeling approach, and the designed peptides have potential uses as diagnostic tools or cancer therapeutics.

Roles of the C-terminal peptide binding domain of human inducible HSP70 in focal ischemic brain injury

2005 ◽  
Vol 25 (1_suppl) ◽  
pp. S53-S53
Author(s):  
Yunjuan Sun ◽  
Yibing Ouyang ◽  
Lijun Xu ◽  
Rona G Giffard
Keyword(s):  
Brain Injury ◽  
Peptide Binding ◽  
Binding Domain ◽  
Ischemic Brain Injury ◽  
Ischemic Brain

Rapid Elaboration of Fragments into Leads Applied to Bromodomain-3 Extra Terminal Domain

2020 ◽  
Author(s):  
Luke Adams ◽  
Lorna E. Wilkinson-White ◽  
Menachem J. Gunzburg ◽  
Stephen J. Headey ◽  
Martin J. Scanlon ◽  
...  
Keyword(s):  
Binding Site ◽  
Systematic Approach ◽  
Structural Information ◽  
Peptide Binding ◽  
Chemical Diversity ◽  
Chemical Probes ◽  
Protein Targets ◽  
Structure Activity ◽  
Peptide Binding Site ◽  
Selection Of

The development of low-affinity fragment hits into higher affinity leads is a major hurdle in fragment-based drug design. Here we demonstrate an approach for the Rapid Elaboration of Fragments into Leads (REFiL) applying an integrated workflow that provides a systematic approach to generate higher-affinity binders without the need for structural information. The workflow involves the selection of commercial analogues of fragment hits to generate preliminary structure-activity relationships. This is followed by parallel microscale chemistry using chemoinformatically designed reagent libraries to rapidly explore chemical diversity. Upon completion of a fragment screen against Bromodomain-3 extra terminal (BRD3-ET) domain we applied the REFiL workflow, which allowed us to develop a series of tetrahydrocarbazole ligands that bind to the peptide binding site of BRD3-ET. With REFiL we were able to rapidly improve binding affinity >30-fold. The REFiL workflow can be applied readily to a broad range of protein targets without the need of a structure, allowing the efficient evolution of low-affinity fragments into higher affinity leads and chemical probes.<br>

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