scholarly journals Small Molecule Ligands Define a Binding Site on the Immune Regulatory Protein B7.1

2001 ◽  
Vol 277 (9) ◽  
pp. 7363-7368 ◽  
Author(s):  
David V. Erbe ◽  
Suyue Wang ◽  
Yuzhe Xing ◽  
James F. Tobin
Keyword(s):  
Binding Site ◽  
Small Molecule ◽  
Regulatory Protein ◽  
Small Molecule Ligands

scholarly journals If You Cannot Win Them, Join Them: Understanding New Ways to Target STAT3 by Small Molecules

2019 ◽  
Author(s):  
Francesc Sabanés ◽  
Joao Victor de Souza Cunha ◽  
Roger Estrada-Tejedor ◽  
Agnieszka K Bronowska
Keyword(s):  
Dna Binding ◽  
Binding Site ◽  
Small Molecule ◽  
Poor Prognosis ◽  
Critical Role ◽  
Binding Mode ◽  
Pharmacological Intervention ◽  
Inhibition Mechanism ◽  
Structure Dynamics ◽  
Small Molecule Ligands

<p>Signal transducer activator of transcription 3 (STAT3) is among the most investigated oncogenic transcription factors, as it is highly associated with cancer initiation, progression, metastasis, chemoresistance, and immune evasion. The recent evidence from both preclinical and clinical studies have demonstrated that STAT3 plays a critical role in several malignancies associated with poor prognosis such as glioblastoma and triple-negative breast cancer (TNBC), and STAT3 inhibitors have shown efficacy in inhibiting cancer growth and metastasis. Constitutive activation of STAT3 by mutations occurs frequently in tumour cells, and directly contributes to many malignant phenotypes. Unfortunately, detailed structural biology studies on STAT3 as well as target-based drug discovery efforts have been hampered by difficulties in the expression and purification of the full length STAT3 and a lack of ligand-bound crystal structures.</p><p>Considering these, molecular modelling and simulations offer an attractive strategy for the assessment of “druggability” of STAT3 dimers and allow investigations of reported activating and inhibiting STAT3 mutants at the atomistic level of detail. In the present study, we focused on the effects exerted by reported STAT3 mutations on the protein structure, dynamics, DNA binding and dimerisation, thus linking structure, dynamics, energetics, and the biological function. By employing atomistic molecular dynamics (MD) and umbrella sampling (US) simulations to a series of human STAT3 dimer, which comprised wild-type protein and four mutations; we explained the modulation of STAT3 activity by these mutations. Counter-intuitively, our results show that D570K inhibitory mutation exerts its effect by enhancing rather than weakening STAT3-DNA interactions, which interferes with the DNA release by the protein dimer and thus inhibits STAT3 function as a transcription factor. We mapped the binding site and characterised the binding mode of a clinical candidate napabucasin/BBI-608 at STAT3, which resembles the effect of D570K mutation. We also discovered a novel binding site at STAT3 DNA binding domain, amenable to bind small molecule ligands.</p><p>Our results contribute to understanding the activation/inhibition mechanism of STAT3, to explain the molecular mechanism of STAT3 inhibition by napabucasin/BBI-608. In this study, alongside the characterisation of the BBI-608 binding mode, we mapped a novel binding sites amenable to bind small molecule ligands, which may pave the way to design novel STAT3 inhibitors and to suggest new strategies for pharmacological intervention to combat cancers associated with poor prognosis.</p>

scholarly journals Fragment-Based Ligand-Protein Contact Statistics: Application to Docking Simulations

2019 ◽  
Vol 20 (10) ◽  
pp. 2499 ◽  
Author(s):  
Gabriele Macari ◽  
Daniele Toti ◽  
Carlo Del Moro ◽  
Fabio Polticelli
Keyword(s):  
Binding Site ◽  
Small Molecule ◽  
Test Case ◽  
Scoring Functions ◽  
Docking Simulations ◽  
Starting Point ◽  
Small Molecule Ligands ◽  
Simple Potential ◽  
Recognition Software ◽  
Site Recognition

In this work, the information contained in the contacts between fragments of small-molecule ligands and protein residues has been collected and its exploitability has been verified by using the scoring of docking simulations as a test case for bringing about a proof of concept. Contact statistics between small-molecule fragments and binding site residues were collected and analyzed using a dataset composed of 200,000+ binding sites and associated ligands, derived from the database of the LIBRA ligand binding site recognition software, as a starting point. The fragments were generated by applying the decomposition algorithm implemented in BRICS. A simple “potential” based on the contact frequencies was tested against the CASF-2013 benchmark; its performance was then evaluated through the rescoring of docking poses generated for the DUD-E dataset. The results obtained indicate that this approach, its simplicity notwithstanding, yields promising results that are comparable, and in some cases, superior, to those obtained with other, more complex scoring functions.

scholarly journals Analysis of Small Molecule Ligands Targeting the HIV-1 Matrix Protein-RNA Binding Site

2012 ◽  
Vol 288 (1) ◽  
pp. 666-676 ◽  
Author(s):  
Ayna Alfadhli ◽  
Henry McNett ◽  
Jacob Eccles ◽  
Seyram Tsagli ◽  
Colleen Noviello ◽  
...  
Keyword(s):  
Binding Site ◽  
Small Molecule ◽  
Matrix Protein ◽  
Rna Binding ◽  
Small Molecule Ligands ◽  
Hiv 1

scholarly journals If You Cannot Win Them, Join Them: Understanding New Ways to Target STAT3 by Small Molecules

2019 ◽  
Author(s):  
Francesc Sabanés ◽  
Joao Victor de Souza Cunha ◽  
Roger Estrada-Tejedor ◽  
Agnieszka K Bronowska
Keyword(s):  
Dna Binding ◽  
Binding Site ◽  
Small Molecule ◽  
Poor Prognosis ◽  
Critical Role ◽  
Binding Mode ◽  
Pharmacological Intervention ◽  
Inhibition Mechanism ◽  
Structure Dynamics ◽  
Small Molecule Ligands

<p>Signal transducer activator of transcription 3 (STAT3) is among the most investigated oncogenic transcription factors, as it is highly associated with cancer initiation, progression, metastasis, chemoresistance, and immune evasion. The recent evidence from both preclinical and clinical studies have demonstrated that STAT3 plays a critical role in several malignancies associated with poor prognosis such as glioblastoma and triple-negative breast cancer (TNBC), and STAT3 inhibitors have shown efficacy in inhibiting cancer growth and metastasis. Constitutive activation of STAT3 by mutations occurs frequently in tumour cells, and directly contributes to many malignant phenotypes. Unfortunately, detailed structural biology studies on STAT3 as well as target-based drug discovery efforts have been hampered by difficulties in the expression and purification of the full length STAT3 and a lack of ligand-bound crystal structures.</p><p>Considering these, molecular modelling and simulations offer an attractive strategy for the assessment of “druggability” of STAT3 dimers and allow investigations of reported activating and inhibiting STAT3 mutants at the atomistic level of detail. In the present study, we focused on the effects exerted by reported STAT3 mutations on the protein structure, dynamics, DNA binding and dimerisation, thus linking structure, dynamics, energetics, and the biological function. By employing atomistic molecular dynamics (MD) and umbrella sampling (US) simulations to a series of human STAT3 dimer, which comprised wild-type protein and four mutations; we explained the modulation of STAT3 activity by these mutations. Counter-intuitively, our results show that D570K inhibitory mutation exerts its effect by enhancing rather than weakening STAT3-DNA interactions, which interferes with the DNA release by the protein dimer and thus inhibits STAT3 function as a transcription factor. We mapped the binding site and characterised the binding mode of a clinical candidate napabucasin/BBI-608 at STAT3, which resembles the effect of D570K mutation. We also discovered a novel binding site at STAT3 DNA binding domain, amenable to bind small molecule ligands.</p><p>Our results contribute to understanding the activation/inhibition mechanism of STAT3, to explain the molecular mechanism of STAT3 inhibition by napabucasin/BBI-608. In this study, alongside the characterisation of the BBI-608 binding mode, we mapped a novel binding sites amenable to bind small molecule ligands, which may pave the way to design novel STAT3 inhibitors and to suggest new strategies for pharmacological intervention to combat cancers associated with poor prognosis.</p>

scholarly journals Allergens and their associated small molecule ligands ‐ their dual role in sensitization

Allergy ◽  
2021 ◽  
Author(s):  
Maksymilian Chruszcz ◽  
Fook Tim Chew ◽  
Karin Hoffmann‐Sommergruber ◽  
Barry K. Hurlburt ◽  
Geoffrey A. Mueller ◽  
...  
Keyword(s):  
Small Molecule ◽  
Dual Role ◽  
Small Molecule Ligands

scholarly journals Structural Insight into the Two-Step Mechanism of PAI-1 Inhibition by Small Molecule TM5484

2021 ◽  
Vol 22 (3) ◽  
pp. 1482 ◽  
Author(s):  
Machteld Sillen ◽  
Toshio Miyata ◽  
Douglas E. Vaughan ◽  
Sergei V. Strelkov ◽  
Paul J. Declerck
Keyword(s):  
Binding Site ◽  
Small Molecule ◽  
Intracellular Signaling ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Joint Region ◽  
Flexible Joint ◽  
Step Mechanism ◽  
Pai 1

Plasminogen activator inhibitor-1 (PAI-1), a key regulator of the fibrinolytic system, is the main physiological inhibitor of plasminogen activators. By interacting with matrix components, including vitronectin (Vn), PAI-1 plays a regulatory role in tissue remodeling, cell migration, and intracellular signaling. Emerging evidence points to a role for PAI-1 in various pathological conditions, including cardiovascular diseases, cancer, and fibrosis. Targeting PAI-1 is therefore a promising therapeutic strategy in PAI-1-related pathologies. A class of small molecule inhibitors including TM5441 and TM5484, designed to bind the cleft in the central β-sheet A of PAI-1, showed to be potent PAI-1 inhibitors in vivo. However, their binding site has not yet been confirmed. Here, we report two X-ray crystallographic structures of PAI-1 in complex with TM5484. The structures revealed a binding site at the flexible joint region, which is distinct from the presumed binding site. Based on the structural analysis and biochemical data we propose a mechanism for the observed dose-dependent two-step mechanism of PAI-1 inhibition. By binding to the flexible joint region in PAI-1, TM5484 might restrict the structural flexibility of this region, thereby inducing a substrate form of PAI-1 followed by a conversion to an inert form.

scholarly journals Functional homology between the yeast regulatory proteins GAL4 and LAC9: LAC9-mediated transcriptional activation in Kluyveromyces lactis involves protein binding to a regulatory sequence homologous to the GAL4 protein-binding site.

1987 ◽  
Vol 7 (12) ◽  
pp. 4400-4406 ◽  
Author(s):  
K D Breunig ◽  
P Kuger
Keyword(s):  
Protein Binding ◽  
Binding Site ◽  
Transcriptional Activation ◽  
Kluyveromyces Lactis ◽  
Regulatory Protein ◽  
Binding Activity ◽  
Protein Binding Site ◽  
Regulatory Sequence ◽  
Functional Homology ◽  
Beta Galactosidase

As shown previously, the beta-galactosidase gene of Kluyveromyces lactis is transcriptionally regulated via an upstream activation site (UASL) which contains a sequence homologous to the GAL4 protein-binding site in Saccharomyces cerevisiae (M. Ruzzi, K.D. Breunig, A.G. Ficca, and C.P. Hollenberg, Mol. Cell. Biol. 7:991-997, 1987). Here we demonstrate that the region of homology specifically binds a K. lactis regulatory protein. The binding activity was detectable in protein extracts from wild-type cells enriched for DNA-binding proteins by heparin affinity chromatography. These extracts could be used directly for DNase I and exonuclease III protection experiments. A lac9 deletion strain, which fails to induce the beta-galactosidase gene, did not contain the binding factor. The homology of LAC9 protein with GAL4 (J.M. Salmeron and S. A. Johnston, Nucleic Acids Res. 14:7767-7781, 1986) strongly suggests that LAC9 protein binds directly to UASL and plays a role similar to that of GAL4 in regulating transcription.

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