Model Identifier
BIOMD0000000629
Short description
Haffez2017 - RAR interaction with synthetic
analogues
This model is described in the article:
MedChemComm
Abstract:
All-trans-retinoic acid (ATRA) and its synthetic analogues EC23 and EC19 direct cellular differentiation by interacting as ligands for the retinoic acid receptor (RARα, β and γ) family of nuclear receptor proteins. To date, a number of crystal structures of natural and synthetic ligands complexed to their target proteins have been solved, providing molecular level snap-shots of ligand binding. However, a deeper understanding of receptor and ligand flexibility and conformational freedom is required to develop stable and effective ATRA analogues for clinical use. Therefore, we have used molecular modelling techniques to define RAR interactions with ATRA and two synthetic analogues, EC19 and EC23, and compared their predicted biochemical activities to experimental measurements of relative ligand affinity and recruitment of coactivator proteins. A comprehensive molecular docking approach that explored the conformational space of the ligands indicated that ATRA is able to bind the three RAR proteins in a number of conformations with one extended structure being favoured. In contrast the biologically-distinct isomer, 9-cis-retinoic acid (9CRA), showed significantly less conformational flexibility in the RAR binding pockets. These findings were used to inform docking studies of the synthetic retinoids EC23 and EC19, and their respective methyl esters. EC23 was found to be an excellent mimic for ATRA, and occupied similar binding modes to ATRA in all three target RAR proteins. In comparison, EC19 exhibited an alternative binding mode which reduces the strength of key polar interactions in RARα/γ but is well-suited to the larger RARβ binding pocket. In contrast, docking of the corresponding esters revealed the loss of key polar interactions which may explain the much reduced biological activity. Our computational results were complemented using an in vitro binding assay based on FRET measurements, which showed that EC23 was a strongly binding, pan-agonist of the RARs, while EC19 exhibited specificity for RARβ, as predicted by the docking studies. These findings can account for the distinct behaviour of EC23 and EC19 in cellular differentiation assays, and additionally, the methods described herein can be further applied to the understanding of the molecular basis for the selectivity of different retinoids to RARα, β and γ.
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Format
SBML
(L2V4)
Related Publication
-
The molecular basis of the interactions between synthetic retinoic acid analogues and the retinoic acid receptors
- Hesham Haffez, David R. Chisholm, Roy Valentine, Ehmke Pohl, Christopher Redfern and Andrew Whiting
- MedChemComm , DOI: 10.1039/C6MD00680A
- Department of Chemistry Durham University, Department of Biosciences & Biophysical Sciences,Durham University, Northern Institute for Cancer Research, Medical School, Newcastle University, Department of Biochemistry and Molecular Biology, Pharmacy College, Helwan University and High Force Research Ltd., Bowburn North Industrial Estate, Bowburn, Durham
- All-trans-retinoic acid (ATRA) and its synthetic analogues EC23 and EC19 direct cellular differentiation by interacting as ligands for the retinoic acid receptor (RARα, β and γ) family of nuclear receptor proteins. To date, a number of crystal structures of natural and synthetic ligands complexed to their target proteins have been solved, providing molecular level snap-shots of ligand binding. However, a deeper understanding of receptor and ligand flexibility and conformational freedom is required to develop stable and effective ATRA analogues for clinical use. Therefore, we have used molecular modelling techniques to define RAR interactions with ATRA and two synthetic analogues, EC19 and EC23, and compared their predicted biochemical activities to experimental measurements of relative ligand affinity and recruitment of coactivator proteins. A comprehensive molecular docking approach that explored the conformational space of the ligands indicated that ATRA is able to bind the three RAR proteins in a number of conformations with one extended structure being favoured. In contrast the biologically-distinct isomer, 9-cis-retinoic acid (9CRA), showed significantly less conformational flexibility in the RAR binding pockets. These findings were used to inform docking studies of the synthetic retinoids EC23 and EC19, and their respective methyl esters. EC23 was found to be an excellent mimic for ATRA, and occupied similar binding modes to ATRA in all three target RAR proteins. In comparison, EC19 exhibited an alternative binding mode which reduces the strength of key polar interactions in RARα/γ but is well-suited to the larger RARβ binding pocket. In contrast, docking of the corresponding esters revealed the loss of key polar interactions which may explain the much reduced biological activity. Our computational results were complemented using an in vitro binding assay based on FRET measurements, which showed that EC23 was a strongly binding, pan-agonist of the RARs, while EC19 exhibited specificity for RARβ, as predicted by the docking studies. These findings can account for the distinct behaviour of EC23 and EC19 in cellular differentiation assays, and additionally, the methods described herein can be further applied to the understanding of the molecular basis for the selectivity of different retinoids to RARα, β and γ.
Contributors
Hesham Haffez, administrator
Metadata information
is
hasTaxon
isPartOf
isDescribedBy
Curation status
Curated
Tags
| Name | Description | Size | Actions |
|---|---|---|---|
Model files |
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| BIOMD0000000629_url.xml | SBML L2V4 representation of Haffez2017 - RAR interaction with synthetic analogues | 31.51 KB | Preview | Download |
Additional files |
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| BIOMD0000000629.pdf | Auto-generated PDF file | 156.18 KB | Preview | Download |
| BIOMD0000000629.m | Auto-generated Octave file | 3.58 KB | Preview | Download |
| BIOMD0000000629.sci | Auto-generated Scilab file | 1.89 KB | Preview | Download |
| BIOMD0000000629.png | Auto-generated Reaction graph (PNG) | 16.28 KB | Preview | Download |
| BIOMD0000000629_urn.xml | Auto-generated SBML file with URNs | 31.33 KB | Preview | Download |
| BIOMD0000000629-biopax3.owl | Auto-generated BioPAX (Level 3) | 11.46 KB | Preview | Download |
| BIOMD0000000629.xpp | Auto-generated XPP file | 1.72 KB | Preview | Download |
| BIOMD0000000629.vcml | Auto-generated VCML file | 58.72 KB | Preview | Download |
| SigmaplotFiles.zip | These Files can be used with sigmaplot to reproduce the figures in the paper | 84.90 KB | Preview | Download |
| BIOMD0000000629-biopax2.owl | Auto-generated BioPAX (Level 2) | 8.51 KB | Preview | Download |
| BIOMD0000000629.svg | Auto-generated Reaction graph (SVG) | 5.83 KB | Preview | Download |
- Model originally submitted by : Hesham Haffez
- Submitted: 24-Feb-2017 20:26:15
- Last Modified: 21-Dec-2018 18:20:32
Revisions
-
Version: 3
- Submitted on: 21-Dec-2018 18:20:32
- Submitted by: administrator
- With comment: Include the additional files provided by the submitter in the original submission: SigmaplotFiles.zip
-
Version: 2
- Submitted on: 20-Apr-2017 15:49:49
- Submitted by: Hesham Haffez
- With comment: Current version of Haffez2017 - RAR interaction with synthetic analogues
-
Version: 1
- Submitted on: 24-Feb-2017 20:26:15
- Submitted by: Hesham Haffez
- With comment: Original import of RAR-retinoids biomodel
Legends
: Variable used inside SBML models
: Variable used inside SBML models
Species
| Species | Initial Concentration/Amount |
|---|---|
| Ligand all-trans-retinoic acid |
5.0E-4 μmol |
| Ligand-Receptor all-trans-retinoic acid ; Retinoic acid receptor alpha |
0.0 μmol |
| Receptor Retinoic acid receptor alpha |
0.0035 μmol |
| CoActivator fluorescin ; peptide |
30.0 μmol |
| Ligand-Receptor-CoActivator all-trans-retinoic acid ; Retinoic acid receptor alpha |
0.0 μmol |
Reactions
| Reactions | Rate | Parameters |
|---|---|---|
| (Ligand + Receptor) => (Ligand-Receptor) ([all-trans-retinoic acid] + [Retinoic acid receptor alpha]) => ([all-trans-retinoic acid; Retinoic acid receptor alpha]) |
RAR_retinoids*(k1*L*R-k2*LR) RAR_retinoids*(k1*[all-trans-retinoic acid]*[Retinoic acid receptor alpha]-k2*[all-trans-retinoic acid; Retinoic acid receptor alpha]) |
k1=0.6; k2=0.1 |
| (Ligand-Receptor + CoActivator) => (Ligand-Receptor-CoActivator) ([all-trans-retinoic acid; Retinoic acid receptor alpha] + [fluorescin; peptide]) => ([all-trans-retinoic acid; Retinoic acid receptor alpha]) |
RAR_retinoids*(k1*LR*CA-k2*LRCA) RAR_retinoids*(k1*[all-trans-retinoic acid; Retinoic acid receptor alpha]*[fluorescin; peptide]-k2*[all-trans-retinoic acid; Retinoic acid receptor alpha]) |
k2=0.2; k1=0.014 |
Curator's comment:
(added: 17 Mar 2017, 14:13:15, updated: 17 Mar 2017, 14:13:15)
(added: 17 Mar 2017, 14:13:15, updated: 17 Mar 2017, 14:13:15)
We used COPASI 4.19 (Build 140) to reproduce figure 14 d from the paper. The simulation was run on COPASI and the plot was generated using R.
The authors in the original paper have used COPASI to calculate the steady state values. These values were then used on SigmaPlot and a 3-parameter sigmoidal curve f = min + (max-min)/(1+10^(logEC50-x)) was used in generating this figure.