Biological activity and ligand binding mode to the progesterone receptor of A-homo analogues of progesterone

2011 ◽  
Vol 19 (5) ◽  
pp. 1683-1691 ◽  
Author(s):  
Lautaro D. Alvarez ◽  
María V. Dansey ◽  
Marcelo A. Martí ◽  
Paola Y. Bertucci ◽  
Pablo H. Di Chenna ◽  
...  
Keyword(s):  
Biological Activity ◽  
Progesterone Receptor ◽  
Ligand Binding ◽  
Binding Mode

Binding Modes of Ligands Using Enhanced Sampling (BLUES): Rapid Decorrelation of Ligand Binding Modes Using Nonequilibrium Candidate Monte Carlo

2017 ◽  
Author(s):  
Samuel Gill ◽  
Nathan M. Lim ◽  
Patrick Grinaway ◽  
Ariën S. Rustenburg ◽  
Josh Fass ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Ligand Binding ◽  
Binding Mode ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Binding Modes ◽  
Enhanced Sampling ◽  
Recent Success ◽  
Multiple Binding ◽  
Proper Sampling

<div>Accurately predicting protein-ligand binding is a major goal in computational chemistry, but even the prediction of ligand binding modes in proteins poses major challenges. Here, we focus on solving the binding mode prediction problem for rigid fragments. That is, we focus on computing the dominant placement, conformation, and orientations of a relatively rigid, fragment-like ligand in a receptor, and the populations of the multiple binding modes which may be relevant. This problem is important in its own right, but is even more timely given the recent success of alchemical free energy calculations. Alchemical calculations are increasingly used to predict binding free energies of ligands to receptors. However, the accuracy of these calculations is dependent on proper sampling of the relevant ligand binding modes. Unfortunately, ligand binding modes may often be uncertain, hard to predict, and/or slow to interconvert on simulation timescales, so proper sampling with current techniques can require prohibitively long simulations. We need new methods which dramatically improve sampling of ligand binding modes. Here, we develop and apply a nonequilibrium candidate Monte Carlo (NCMC) method to improve sampling of ligand binding modes.</div><div><br></div><div>In this technique the ligand is rotated and subsequently allowed to relax in its new position through alchemical perturbation before accepting or rejecting the rotation and relaxation as a nonequilibrium Monte Carlo move. When applied to a T4 lysozyme model binding system, this NCMC method shows over two orders of magnitude improvement in binding mode sampling efficiency compared to a brute force molecular dynamics simulation. This is a first step towards applying this methodology to pharmaceutically relevant binding of fragments and, eventually, drug-like molecules. We are making this approach available via our new Binding Modes of Ligands using Enhanced Sampling (BLUES) package which is freely available on GitHub.</div>

Binding Modes of Ligands Using Enhanced Sampling (BLUES): Rapid Decorrelation of Ligand Binding Modes Using Nonequilibrium Candidate Monte Carlo

2018 ◽  
Author(s):  
Samuel Gill ◽  
Nathan M. Lim ◽  
Patrick Grinaway ◽  
Ariën S. Rustenburg ◽  
Josh Fass ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Ligand Binding ◽  
Binding Mode ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Binding Modes ◽  
Enhanced Sampling ◽  
Recent Success ◽  
Multiple Binding ◽  
Proper Sampling

<div>Accurately predicting protein-ligand binding is a major goal in computational chemistry, but even the prediction of ligand binding modes in proteins poses major challenges. Here, we focus on solving the binding mode prediction problem for rigid fragments. That is, we focus on computing the dominant placement, conformation, and orientations of a relatively rigid, fragment-like ligand in a receptor, and the populations of the multiple binding modes which may be relevant. This problem is important in its own right, but is even more timely given the recent success of alchemical free energy calculations. Alchemical calculations are increasingly used to predict binding free energies of ligands to receptors. However, the accuracy of these calculations is dependent on proper sampling of the relevant ligand binding modes. Unfortunately, ligand binding modes may often be uncertain, hard to predict, and/or slow to interconvert on simulation timescales, so proper sampling with current techniques can require prohibitively long simulations. We need new methods which dramatically improve sampling of ligand binding modes. Here, we develop and apply a nonequilibrium candidate Monte Carlo (NCMC) method to improve sampling of ligand binding modes.</div><div><br></div><div>In this technique the ligand is rotated and subsequently allowed to relax in its new position through alchemical perturbation before accepting or rejecting the rotation and relaxation as a nonequilibrium Monte Carlo move. When applied to a T4 lysozyme model binding system, this NCMC method shows over two orders of magnitude improvement in binding mode sampling efficiency compared to a brute force molecular dynamics simulation. This is a first step towards applying this methodology to pharmaceutically relevant binding of fragments and, eventually, drug-like molecules. We are making this approach available via our new Binding Modes of Ligands using Enhanced Sampling (BLUES) package which is freely available on GitHub.</div>

Development and evaluation of an immunoenzymometric assay for the chicken progesterone receptor

1991 ◽  
Vol 129 (2) ◽  
pp. 189-196 ◽  
Author(s):  
M. K. Bläuer ◽  
P. J. Tuohimaa ◽  
P. J. Vilja
Keyword(s):  
Monoclonal Antibodies ◽  
Small Intestine ◽  
Horseradish Peroxidase ◽  
Progesterone Receptor ◽  
Ligand Binding ◽  
Binding Assay ◽  
Ligand Binding Assay ◽  
Coefficients Of Variation ◽  
First Time ◽  
Determination Range

ABSTRACT A specific and sensitive immunoenzymometric assay (IEMA) was developed for measuring the quantity of chicken progesterone receptor (PR) in tissue cytosol. The assay uses two monoclonal antibodies to the PR. One is used to capture the PR. The second (labelled with biotin) reacts first with the captured receptor and subsequently with avidin-labelled horseradish peroxidase to provide an enzymatic end-point. The method has a determination range from 0·3 to 60 pmol/l. Intra- and interassay coefficients of variation were 3·7% and 9·0% respectively. The assay can be performed with equal results as a rapid (3 h) or an overnight procedure. The IEMA is convenient, especially for signal measurement and the calculation of results. No ultracentrifugation of samples is needed, since the IEMA can be performed on low-speed cytosol samples. Assay results correlated well (r = 0·927) with those obtained by the conventional ligand-binding assay used in our laboratory. Similar results were obtained with the IEMA and the ligand-binding assay after exposure of cytosol samples to increased temperatures: at 20 °C the PR remained stable for the 4-h period examined, whereas at 37 °C almost complete degradation of the PR was observed in 30 min. Being more than 100 times as sensitive as the ligand-binding assay, the IEMA enabled the quantification of PR for the first time in such tissues as the bursa and small intestine even of immature animals. Journal of Endocrinology (1991) 129, 189–196

Monitoring the Ligand Binding Mode by Proton NMR Chemical Shift Differences

ChemMedChem ◽  
2006 ◽  
Vol 1 (11) ◽  
pp. 1197-1199 ◽  
Author(s):  
Srisunder Subramaniam ◽  
Stephen L. Briggs ◽  
Allen D. Kline
Keyword(s):  
Chemical Shift ◽  
Ligand Binding ◽  
Proton Nmr ◽  
Binding Mode ◽  
Nmr Chemical Shift

scholarly journals Visible-Light Photoswitching of G-Quadruplex Ligand Binding Mode Allows Reversible Control of G-Tetrad Structure

2020 ◽  
Author(s):  
Michael O'Hagan ◽  
Javier Ramos Soriano ◽  
Susanta Haldar ◽  
Juan Carlos Morales ◽  
Adrian Mulholland ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Visible Light ◽  
Uv Light ◽  
Binding Mode ◽  
High Energy ◽  
Light Sources ◽  
Biologically Relevant ◽  
G Quadruplex ◽  
Potential Applications ◽  
Robust Regulation

<div><p>Photoresponsive ligands for G-quadruplex oligonucleotides (G4) offer exciting opportunities for the reversible regulation of these assemblies with potential applications in biological chemistry and responsive nanotechnology. However, achieving the robust regulation of G4 ligand activity with low-energy visible light sources that are easily accessible and compatible with biological systems remains a significant challenge to realizing these applications. Herein, we report the G4-binding properties of a photoresponsive dithienylethene (DTE). We demonstrate the first example of G4-specific acceleration of the photoswitching kinetics of a small molecule and the visible-light mediated switching of the G4 ligand binding mode in physiologically-relevant conditions, which in turn allows control over the G4 tetrad structure of telomeric G4 in potassium buffer. The process is fully reversible and avoids the need for high-energy UV light. This affords an efficient, practical and biologically-relevant means of control that may be applied in the generation of new responsive G4/ligand supramolecular systems.</p></div><br>

scholarly journals Ligand Binding and Signaling of HARE/Stabilin-2

Biomolecules ◽  
2019 ◽  
Vol 9 (7) ◽  
pp. 273 ◽  
Author(s):  
Edward N. Harris ◽  
Fatima Cabral
Keyword(s):  
Biological Activity ◽  
Hyaluronic Acid ◽  
Cell Surface ◽  
Ligand Binding ◽  
Antisense Oligonucleotides ◽  
External Environment ◽  
Scavenger Receptors ◽  
Extracellular Material ◽  
Synthetic Drugs ◽  
Multiple Ligands

The Stabilin receptors are a two-member family in the type H class of scavenger receptors. These dynamic receptors bind and internalize multiple ligands from the cell surface for the purpose of clearing extracellular material including some synthetic drugs and for sensing the external environment of the cell. Stabilin-1 was the first receptor to be cloned, though the biological activity of Hyaluronic Acid Receptor for Endocytosis (HARE)/Stabilin-2 was observed about 10 years prior to the cloning of Stabilin-1. Stabilin-1 has a more diverse expression profile among the tissues than HARE/Stabilin-2. This review will focus on HARE/Stabilin-2 and its interactions with hyaluronan, heparin, and phosphorothioate antisense oligonucleotides and what is known about how this receptor participates in signaling upon ligand binding.

scholarly journals X-ray Structures of Progesterone Receptor Ligand Binding Domain in Its Agonist State Reveal Differing Mechanisms for Mixed Profiles of 11β-Substituted Steroids

2012 ◽  
Vol 287 (24) ◽  
pp. 20333-20343 ◽  
Author(s):  
Scott J. Lusher ◽  
Hans C. A. Raaijmakers ◽  
Diep Vu-Pham ◽  
Bert Kazemier ◽  
Rolien Bosch ◽  
...  
Keyword(s):  
Progesterone Receptor ◽  
Ligand Binding ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Receptor Ligand ◽  
X Ray
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