Hot-spot mimicry of a cytokine receptor by a small molecule

Thanos, Christopher D.; DeLano, Warren L.; Wells, James A.

doi:10.1073/pnas.0607058103

Cited by 133 publications

(122 citation statements)

References 34 publications

(39 reference statements)

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“…In spite of their large size disparity, the polar charge distributions of receptor and small molecule interfaces are very similar (Fig. 8b-d) (Thanos et al 2006). In the receptor:IL-2 interaction, the electrostatic fields are defined by a string of acidic groups (glutamate and aspartic acid) on IL-2Ra and a basic Arg 36 that map onto complementary basic (Lys 35, Arg 38) and acidic (Glu 62) patches, respectively, on the surface of IL-2.…”

Section: Comparison Of Small-molecule and Protein Interactions With Il-2mentioning

confidence: 92%

“…Through these studies, the small-molecule-binding potential of IL-2 was revealed to be more subtle and dynamic than anticipated Hyde et al 2003;Waal et al 2005;Arkin et al 2003;Thanos et al 2003Thanos et al , 2006. The X-ray structure of the IL-2:Ro26-4550 complex displays marked alterations in protein conformation from unliganded IL-2 .…”

Section: Structural Characterization Of Ro26-4550 and The Importance mentioning

confidence: 96%

“…Together with our growing understanding of the trends and rules for small-molecule PPI inhibitor design, these give cause for optimism. Interleukin-2 was among the first successful demonstrations that small molecules could inhibit PPIs Hyde et al 2003;Waal et al 2005;Arkin et al 2003;Thanos et al 2003Thanos et al , 2006, and it remains one of the few examples of a small-molecule mimicking a highly discontinuous epitope. The wealth of structural data gathered in the exploration of IL-2 small-molecule inhibitors has revealed surprising complexity at protein-protein interfaces and serves as a rich model that continues to guide screening and inhibitor design.…”

Section: Introductionmentioning

confidence: 99%

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Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

Wilson

Arkin

2010

Current Topics in Microbiology and Immunology

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Section: Comparison Of Small-molecule and Protein Interactions With Il-2mentioning

confidence: 92%

Section: Structural Characterization Of Ro26-4550 and The Importance mentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

Wilson

Arkin

2010

Current Topics in Microbiology and Immunology

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“…More accurate modeling of side-chain conformational flexibility may also be important for structure-based drug design, when a target protein changes its binding site in response to binding different small molecules 11 . Work by Ranganathan and others [12][13][14][15][16][17][18] has provided intriguing evidence for the existence of "communication pathways" in proteins to facilitate the transmission of signals between allosteric and active sites.…”

Section: Introductionmentioning

confidence: 99%

A Simple Model of Backbone Flexibility Improves Modeling of Side-chain Conformational Variability

Friedland

Linares

Smith

et al. 2008

Journal of Molecular Biology

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The considerable flexibility of side-chains in folded proteins is important for protein stability and function, and may play a role in mediating pathways of energetic connectivity between allosteric sites. While sampling side-chain degrees of freedom has been an integral part of several successful computational protein design methods, the predictions of these approaches have not been directly compared to experimental measurements of side-chain motional amplitudes. In addition, protein design methods generally keep the backbone fixed, an approximation that may substantially limit the ability to accurately model side-chain flexibility. Here we describe a Monte Carlo approach to modeling side-chain conformational variability and validate our method against a large dataset of methyl relaxation order parameters derived from Nuclear Magnetic Resonance experiments (17 proteins and a total of 530 data points). We also evaluate a model of backbone flexibility based on Backrub motions, a type of conformational change frequently observed in ultra-high resolution Xray structures that accounts for correlated side-chain backbone movements. The fixed-backbone model performs reasonably well with an overall rmsd between computed and predicted side-chain order parameters of 0.26. Notably, including backbone flexibility leads to significant © 2008 Elsevier Ltd. All rights reserved. * Corresponding author: Kortemme@cgl.ucsf.edu. AUTHOR CONTRIBUTIONSGDF and TK conceived and designed the experiments. GDF and AJL performed the experiments. GDF, TK, and AJL analyzed the data and wrote the paper. CAS contributed reagents/materials/analysis tools. SUPPORTING INFORMATION AVAILABLEOne figure with population distributions of ubiquitin I13 and L15 chi 1 and chi 2. One table with detailed results from Model 1; one table with results from Models 2 and 3 for nonpolar methyl groups only; and one table with detailed parameter sensitivity results from Model 2.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access

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“…Pharmacological chaperones are small molecules that bind to proteins and stabilize them against thermal denaturation or proteolytic degradation, as well as assisting or preventing certain protein-protein assembly (6)(7)(8). Designing pharmacological chaperones against traditionally "undruggable" protein surfaces relies heavily on the availability of threedimensional structures of the proteins of interests, which are used for the identification of "hotspots" and for the design of ligand mimetic structures (9)(10)(11). A variety of classes of compounds have been shown to be effective pharmacological chaperones, including cofactor mimetics (12), catalytic inhibitors (13), ligand mimetics (14), stabilized helical peptides (15)(16)(17), and small-molecule secondary structure-mimetics (18,19).…”

mentioning

confidence: 99%

Potential pharmacological chaperones targeting cancer-associated MCL-1 and Parkinson disease-associated α-synuclein

Lee

Wang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Pharmacological chaperones are small molecules that bind to proteins and stabilize them against thermal denaturation or proteolytic degradation, as well as assist or prevent certain protein-protein assemblies. These activities are being exploited for the development of treatments for diseases caused by protein instability and/or aberrant protein-protein interactions, such as those found in certain forms of cancers and neurodegenerative diseases. However, designing or discovering pharmacological chaperones for specific targets is challenging because of the relatively featureless protein target surfaces, the lack of suitable chemical libraries, and the shortage of efficient highthroughput screening methods. In this study, we attempted to address all these challenges by synthesizing a diverse library of small molecules that mimic protein α-helical secondary structures commonly found in protein-protein interaction surfaces. This was accompanied by establishing a facile "on-bead" high-throughput screening method that allows for rapid and efficient discovery of potential pharmacological chaperones and for identifying novel chaperones/ inhibitors against a cancer-associated protein, myeloid cell leukemia 1 (MCL-1), and a Parkinson disease-associated protein, α-synuclein. Our data suggest that the compounds and methods described here will be useful tools for the development of pharmaceuticals for complexdisease targets that are traditionally deemed "undruggable." chemical biology | drug discovery | helical mimetic

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Hot-spot mimicry of a cytokine receptor by a small molecule

Abstract: Protein-protein complexes remain enticing, but extremely challenging, targets for small-molecule drug discovery. In a rare example described earlier, a high-affinity small molecule, SP4206 (

Cited by 133 publications

References 34 publications

Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

A Simple Model of Backbone Flexibility Improves Modeling of Side-chain Conformational Variability

Potential pharmacological chaperones targeting cancer-associated MCL-1 and Parkinson disease-associated α-synuclein

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