|Year : 2010 | Volume
| Issue : 2 | Page : 139-141
Ligand binding prediction for BRCA1, a key molecule in the pathogensis of breast cancer
Wiwanitkit House, Bangkhae, Bangkok, 10160, Thailand
|Date of Web Publication||5-May-2010|
Wiwanitkit House, Bangkhae, Bangkok, 10160
Source of Support: None, Conflict of Interest: None
Background : Cell adhesion plays a pivotal role in diverse biological processes that occur in oncogenesis. BRCA1 was the first breast cancer susceptibility gene to be successfully identified and cloned. The role of BRCA1 as a predictive marker of chemotherapy response in breast cancer is proposed. Ligand binding is an important factor in the success of chemoprevention. Materials and Methods : In this work, the author performed a ligand-binding prediction for BRCA1 using a new bioinformatics tool. Results : According to this study, 10 strong possible ligands were identified. Conclusion : These sites can be useful for further drug development studies.
Keywords: BRCA1, ligand binding
|How to cite this article:|
Wiwanitkit V. Ligand binding prediction for BRCA1, a key molecule in the pathogensis of breast cancer. Indian J Cancer 2010;47:139-41
| » Introduction|| |
Cell adhesion plays an important role in diverse biological processes that happen in the dynamic setting of the vasculature, including inflammation and cancer metastasis.  Although complex, the naturally occurring processes that have evolved to permit cell adhesion in the vasculature can be exploited to drug carriers to specific targeted cells and tissues.  Ligand binding is an important factor in the carcinogenesis of many malignancies. Ligand-binding analysis becomes an important novel tool for cancer prevention planning. The analysis can be useful for identification of the point of interaction and can be the clue for further molecular docking studies.
The identification of key molecular actors in the mammary oncogenesis may help to better assess the prognosis of the disease in addition to giving new therapeutic targets.  The discovery of the genetics underlying breast cancer has improved the assessment of the individual risk toward the cancer, allowing appropriate planning strategies of screening and prevention.  BRCA1 was the first breast cancer susceptibility gene that could be identified and cloned.  In individuals from high-risk families, mutations in BRCA1 can increase the lifetime risk of developing breast malignancy eight- to 10-fold compared to the general population.  Recently, James et al. proposed the role of BRCA1 as a predictive marker of chemotherapy response in breast cancer.  The proper clinical management of BRCA heterozygotes involves several strategies of primary, secondary and tertiary prevention.  These strategies include risk-reducing surgery, chemoprevention, lifestyle changes and increased surveillance. 
Ligand binding is an important factor for the success of chemoprevention. Recently, Hocking et al. proposed that BRCA1 expression was down-regulated in the absence of mutations in the BRCA1 gene.  They also proposed that the ligand status of the aromatic hydrocarbon receptor modulated transcriptional activation of the BRCA1 promoter by estrogen.  However, the ligand-binding pattern of BRCA1 has never been clarified. In this work, the author performed a ligand-binding prediction for BRCA1 using a new bioinformatics tool.
| » Materials and Methods|| |
Getting the sequence
The Pubmed database was used for datamining of the molecular structure of BRCA1. On conducting literature searches, the sequence of BRCA1 could be derived and used as a template for further determination for ligand binding.
Prediction for ligand binding
Ligand binding for BRCA1 was performed using a novel bioinformatics tool, namely Q-SiteFinder.  This tool is a new computational method of ligand-binding site prediction.  It makes use of the interaction energy between the protein and a simple van der Waals probe to detect energetically favorable binding sites.  Concerning the process, energetically favorable probe sites are clustered due to their spatial proximity and clusters are then ranked according to the sum of interaction energies for sites within each cluster.  In this study, the derived BRCA1 sequence was used as a template for analysis. Ligand-binding areas and their corresponding volumes were identified.  Regarding reliability, the method in this research is widely used in structural genomics studies where protein-binding sites remain unclear, as up to an 86% success rate for unbound proteins appears to be only slightly lower than that of ligand-bound proteins.  The result from the Q-SiteFinder analysis is still in the computational code and requires further visual image construction, as will be further described.
Visualization of the ligand
The result from the Q-SiteFinder analysis was further processed in the format of three-dimensional (3D) molecular structure by a Swiss-Pdb Viewer (GlaxoSmithKline R and D and the Swiss Institute of Bioinformatics). The standard tool provided by the Swiss-Pdb Viewer was also used to construct the finalized figure. In constructing the figure, the specific ligand-binding areas were marked as a sheath plate appearance.
| » Results|| |
The molecular structure of the Brct-C domain from human BRCA1 (1OQA) was derived from primary database searching and was used as a template for further prediction of ligand-binding sites. According to the analysis, 10 ligands at different positions were identified. The ligand-binding site at position 245 had the highest binding property. The results the from analysis are shown in [Table 1] and [Figure 1].
| » Discussion|| |
BRCA1-associated hereditary breast malignancies are diagnosed at a younger age and are known to show biological aggressiveness, such as a high histological grade and frequent aneuploidy, compared to sporadic breast malignancies.  BRCA1 is an important molecule, which is noted for its significant role in the pathogenesis of breast cancer. It is the molecular targets for phytochemicals indole-3-carbinol and genistein in breast malignant cells.  Kang et al. also reported that xenobiotic (TCDD) treatments of breast cancer cells containing reduced levels of BRCA1 caused the transcription factor ARNT to become unstable. 
Analysis of ligand binding within the BRCA1 molecule can be useful for new preventive and therapeutic drug development for breast cancer. Indeed, only a few amino acid changes within this molecule might affect the whole phenotypic function.  Many different mutations are documented in the BRCA1 molecule, including several examples of recurrent mutations, each of which accounts for a significant number of families with heritable cancer predisposition.  With the increasing amount of data provided by both high-throughput sequencing and structural genomics studies, there is a need for new tools to augment functional predictions for interested protein sequences.  Broad descriptions of protein function can be provided by setting the presence of protein domains associated with a particular function.  Here, the author used an advanced bioinformatics tool to analyze the ligand-binding pattern within the BRCA1 molecule.
According to this study, 10 strong possible ligands were identified. Indeed, there are only a few reports on the ligand binding of BRCA1. Recently, Birrane et al. proposed that two prominent histidine residues, His685 and His686, might be ligand-binding sites.  However, several other different alternatives are detected in this work. These sites can be useful for further drug development studies. Prediction of the roles and vulnerable binding descriptions of these sites are planned in the future research.
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