Application and evaluation of molecular docking for aptamer and small molecular interaction - A case study with tetracycline antibiotics.

Molecular docking (MD) analysis is currently the most commonly used theoretical simulation method to investigate the interaction of aptamers (receptors) and small molecules (ligands) and understand the recognition mechanism between them at a molecular level. Using the specific aptamers of tetracycline antibiotics (tetracycline (TET), oxytetracycline (OTC), doxycycline (DOC)) as the docking models, three steady-state aptamers of tertiary structures (SATS) were established for each aptamer with the UNAFold and RNAComposer tools. The binding free energy (BFE), docking score (DS), and binding site (base) of the specific ligands (TET, OTC, and DOC) with their respective SATS were obtained by molecular docking. The results revealed one or more binding sites in the established SATS of the aptamers. The BFE and DS of different binding sites of one specific SATS varied significantly. The results also revealed that the site with the highest BFE represented the most dominant binding site, even if it was not the SATS with minimum energy. The BFE values could also be used to evaluate the affinity and specificity of the aptamer to its target. For the first time, this study proposes a method for MD analysis of the aptamer and its target based on different SATS, clarification of the binding mode, and prediction of the binding sites (bases). This study provides a theoretical basis for tailoring; structural optimization; and base modification of aptamers; identifying aptamers with high affinity and specificity.

One master and two servants: One Zr(â £) with two ligands of TCPP and NH2-BDC form the MOF as the electrochemiluminescence emitter for the biosensing application.

Here we put forward an innovative "one master and two servants" strategy for enhancing the ECL performance. A novel ECL luminophore named Zr-TCPP/NH2-BDC (TCPP@UiO-66-NH2) was synthesized by self-assembly of meso-tetra(4-carboxyphenyl)porphine (TCPP) and 4-aminobenzoic acid (NH2-BDC) with Zr clusters. TCPP@UiO-66-NH2 has a porous structure and a highly ordered structure, which allows the molecular motion of TCPP to be effectively confined, thereby inhibiting nonradiative energy transfer. Importantly, TCPP@UiO-66-NH2 has a higher and more stable ECL signal. To further improve the sensitivity of the sensor, we use polydopamine-coated manganese dioxide (PDA@MnO2), which has a double quenching effect, as the quencher. The nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2-N) is one of the ideal markers for the early diagnosis of COVID-19, and its sensitivity detection is of great significance for the prevention and treatment of COVID-19. Thus, we constructed a quenching-type ECL sensor for the ultrasensitive detection of the SARS-CoV-2-N. Its linear range is 10 fg/mL∼1 µg/mL and the calculated detection limit is 1.4 fg/mL (S/N = 3). The spiked recoveries are 97.40-103.8%, with the relative standard deviations (RSD) under 3.0%. More importantly, the technique offers a viable way to identify and diagnose viral infections early.

Recent progress of SELEX methods for screening nucleic acid aptamers.

Nucleic acid aptamers are oligonucleotide sequences screened by an in vitro methodology called Systematic Evolution of Ligands by Exponential Enrichment (SELEX). Known as "chemical antibodies", aptamers can achieve specific recognition towards the targets through conformational changes with high affinity, and possess multiple attractive features including, but not limited to, easy and inexpensive to prepare by chemical synthesis, relatively stable and low batch-to-batch variability, easy modification and signal amplification, and low immunogenicity. Now, aptamers are attracting researchers' attentions from more than 25 disciplines, and have showed great potential for application and economic benefits in disease diagnosis, environmental detection, food security, drug delivery and discovery. Although some aptamers exist naturally as the ligand-binding elements of riboswitches, SELEX is a recognized method for aptamers screening. After thirty-two years of development, a series of SELEX methods have been investigated and developed, as well as have shown unique advantages to improve sequence performances or to explore screening mechanisms. This review would mainly focus on the novel or improved SELEX methods that are available in the past five years. Firstly, we present a clear overview of the aptamer's history, features, and SELEX development. Then, we highlight the specific examples to emphasize the recent progress of SELEX methods in terms of carrier materials, technical improvements, real sample-improved screening, post-SELEX and other methods, as well as their respects of screening strategies, implementation features, screening parameters. Finally, we discuss the remaining challenges that have the potential to hinder the success of SELEX and aptamers in practical applications, and provide the suggestions and future directions for developing more convenient, efficient, and stable SELEX methods in the future.

Highly bright and stable CsPbBr3 perovskite nanocrystals with amphiphilic polymer binding based dual-readout lateral flow immunoassay for detection of carcinoembryonic antigen.

Rapid and highly sensitive detection of tumor marker (TM) is critical for the early diagnosis and treatment of cancers. Herein, utilizing highly bright and water-stable CsPbBr3 perovskite nanocrystals (NCs) capped with amphiphilic polymer ligand of octylamine-modified polyacrylic acid (OPA) and gold nanoparticles (AuNPs) as reporters, a lateral flow immunoassay (LFIA) strip is developed for fluorescence and colorimetric dual-mode detection of carcinoembryonic antigen (CEA). The prepared CsPbBr3 NCs capped by an amphiphilic polymeric of OPA ligand showed high stability and bright fluorescence. Moreover, the AuNPs immunoprobes were captured with CEA antigen and quench the green fluorescence of CsPbBr3/OPA NCs on the T line due to the inner filter effect (IFE). Therefore, CEA could be quantitative analyzed by the dual-readout of fluorescence and colorimetric signal. The detection limits of CEA can reach as low as 0.023 ng/mL and 0.027 ng/mL for the fluorescence and colorimetric mode, respectively. Good specificity and reproducibility were also demonstrated for this method. Finally, the CsPbBr3/OPA NCs-based LFIA showed good accuracy in detection of CEA level from clinical serum samples. This work firstly enables the application of CsPbBr3 perovskite NCs in a LFIA, displaying great potential in point-of-care clinical diagnosis.

Ratiometric fluorescence aptasensor for the detection of patulin in apple juice based on the octahedral UiO-66-TCPP metal-organic framework and aptamer systems.

Patulin (PAT) is a potentially harmful mycotoxin to human health and is known to contaminate apple juice. In this work, we developed a ratiometric fluorescence aptasensor using tetrakis(4-carboxyphenyl)porphyrin (H2TCPP)-treated octahedral UiO-66-NH2 (defined as UiO-66-TCPP) to detect PAT. This 2-aminoterephthalic acid and H2TCPP functionalized metal-organic framework showed multiple adsorption effects (hydrogen bonding and π-π stacking) on the aptamer (Apt) and served as a quenching material. When the target PAT bound specifically to the Apt, the fluorescence of the 6-carboxyfluorescein-labeled Apt would recover, and the fluorescence of the H2TCPP ligand remained unchanged. This ratiometric fluorescence property improved the accuracy of PAT detection. Moreover, the introduction of the H2TCPP ligand enhanced the quenching efficiency of UiO-66-NH2, thus improving the sensitivity of the fluorescent aptasensor (UiO-66-TCPP vs. UiO-66-NH2: 0.0162 ng/mL vs. 1.8 ng/mL). In addition, we used UiO-66-TCPP to detect PAT in apple juice samples. This work provides a good paradigm for the construction of ratiometric fluorescence aptasensors with high sensitivity and accuracy.

Antiviral Drug Target Identification and Ligand Discovery.

This chapter intends to provide a general overview of web-based resources available for antiviral drug discovery studies. First, we explain how the structure for a potential viral protein target can be obtained and then highlight some of the main considerations in preparing for the application of receptor-based molecular docking techniques. Thereafter, we discuss the resources to search for potential drug candidates (ligands) against this target protein receptor, how to screen them, and preparing their analogue library. We make specific reference to free, online, open-source tools and resources which can be applied for antiviral drug discovery studies.

Protein-Ligand Blind Docking Using CB-Dock2.

Protein-ligand blind docking is a widely used method for studying the binding sites and poses of ligands and receptors in pharmaceutical and biological research. Recently, our new blind docking server named CB-Dock2 has been released and is currently being utilized by researchers worldwide. CB-Dock2 outperforms state-of-the-art methods due to its accuracy in binding site identification and binding pose prediction, which are enabled by its knowledge-based docking engine. This highly automated server offers interactive and intuitive input and output web interfaces, making it an efficient and user-friendly tool for the bioinformatics and cheminformatics communities. This chapter provides a brief overview of the methods, followed by a detailed guide on using the CB-Dock2 server. Additionally, we present a case study that evaluates the performance of protein-ligand blind docking using this tool.

Molecular Dynamics as a Tool for Virtual Ligand Screening.

Rational drug design is essential for new drugs to emerge, especially when the structure of a target protein or nucleic acid is known. To that purpose, high-throughput virtual ligand screening campaigns aim at discovering computationally new binding molecules or fragments to modulate particular biomolecular interactions or biological activities, related to a disease process. The structure-based virtual ligand screening process primarily relies on docking methods which allow predicting the binding of a molecule to a biological target structure with a correct conformation and the best possible affinity. The docking method itself is not sufficient as it suffers from several and crucial limitations (lack of full protein flexibility information, no solvation and ion effects, poor scoring functions, and unreliable molecular affinity estimation).At the interface of computer techniques and drug discovery, molecular dynamics (MD) allows introducing protein flexibility before or after a docking protocol, refining the structure of protein-drug complexes in the presence of water, ions, and even in membrane-like environments, describing more precisely the temporal evolution of the biological complex and ranking these complexes with more accurate binding energy calculations. In this chapter, we describe the up-to-date MD, which plays the role of supporting tools in the virtual ligand screening (VS) process.Without a doubt, using docking in combination with MD is an attractive approach in structure-based drug discovery protocols nowadays. It has proved its efficiency through many examples in the literature and is a powerful method to significantly reduce the amount of required wet experimentations (Tarcsay et al, J Chem Inf Model 53:2990-2999, 2013; Barakat et al, PLoS One 7:e51329, 2012; De Vivo et al, J Med Chem 59:4035-4061, 2016; Durrant, McCammon, BMC Biol 9:71-79, 2011; Galeazzi, Curr Comput Aided Drug Des 5:225-240, 2009; Hospital et al, Adv Appl Bioinforma Chem 8:37-47, 2015; Jiang et al, Molecules 20:12769-12786, 2015; Kundu et al, J Mol Graph Model 61:160-174, 2015; Mirza et al, J Mol Graph Model 66:99-107, 2016; Moroy et al, Future Med Chem 7:2317-2331, 2015; Naresh et al, J Mol Graph Model 61:272-280, 2015; Nichols et al, J Chem Inf Model 51:1439-1446, 2011; Nichols et al, Methods Mol Biol 819:93-103, 2012; Okimoto et al, PLoS Comput Biol 5:e1000528, 2009; Rodriguez-Bussey et al, Biopolymers 105:35-42, 2016; Sliwoski et al, Pharmacol Rev 66:334-395, 2014).

Accelerating Molecular Dynamics Simulations for Drug Discovery.

Accurate prediction of ligand binding thermodynamics and kinetics is crucial in drug design. However, it remains challenging for conventional molecular dynamics (MD) simulations due to sampling issues. Gaussian accelerated MD (GaMD) is an enhanced sampling method that adds a harmonic boost to overcome energy barriers, which has demonstrated significant benefits in exploring protein-ligand interactions. Especially, the ligand GaMD (LiGaMD) applies a selective boost potential to the ligand nonbonded potential energy, significantly improving sampling for ligand binding and dissociation. Furthermore, a selective boost potential is applied to the potential of both ligand and protein residues around binding pocket in LiGaMD2 to further increase the sampling of protein-ligand interaction. LiGaMD and LiGaMD2 simulations could capture repetitive ligand binding and unbinding events within microsecond simulations, allowing to simultaneously characterize ligand binding thermodynamics and kinetics, which is expected to greatly facilitate drug design. In this chapter, we provide a brief review of the status of LiGaMD in drug discovery and outline its usage.

Alchemical Free Energy Workflows for the Computation of Protein-Ligand Binding Affinities.

Alchemical free energy methods can be used for the efficient computation of relative binding free energies during preclinical drug discovery stages. In recent years, this has been facilitated further by the implementation of workflows that enable non-experts to quickly and consistently set up the required simulations. Given the correct input structures, workflows handle the difficult aspects of setting up perturbations, including consistently defining the perturbable molecule, its atom mapping and topology generation, perturbation network generation, running of the simulations via different sampling methods, and analysis of the results. Different academic and commercial workflows are discussed, including FEW, FESetup, FEPrepare, CHARMM-GUI, Transformato, PMX, QLigFEP, TIES, ProFESSA, PyAutoFEP, BioSimSpace, FEP+, Flare, and Orion. These workflows differ in various aspects, such as mapping algorithms or enhanced sampling methods. Some workflows can accommodate more than one molecular dynamics (MD) engine and use external libraries for tasks. Differences between workflows can present advantages for different use cases, however a lack of interoperability of the workflows' components hinders systematic comparisons.

Dual-ligand hydrogen-bonded organic framework: Tailored for mono-phosphopeptides and glycopeptides analysis.

Hydrogen-bonded organic frameworks (HOFs) have emerged as a promising class of materials for applications of separation and enrichment. Utilizing multiple-ligands to construct HOFs is a promising avenue towards the development of structurally stable and functionally diverse frameworks, offering opportunities to create customized binding sites for selective recognition of biomolecules. In recent years, due to the crucial role that protein post-translational modifications (PTMs) play in maintaining protein function and regulating signaling pathways, and the growing recognition of the extensive cross-talk that can occur between PTMs, simultaneous analysis of different types of PTMs represents a requirement of a new generation of enrichment materials. Here, for the first attempt, we report a dual-ligand HOF constructed from borate anion and guanidinium cation for the simultaneous identification of glycopeptides and phosphopeptides, especially mono-phosphopeptides. According to theoretical calculations, the HOF functional sites display a synergistic "matching" effect with mono-phosphopeptides, resulting in a stronger enrichment effect for mono-phosphopeptides as compared to multi-phosphopeptides. Also, due to its high hydrophilicity and boronate affinity, this material can efficiently capture glycoproteins. HOF is set to become an active research direction in the development of highly efficient simultaneous protein enrichment materials, and offers a new approach for comprehensive PTMs analysis.

A pre-oxidized Eu-probe doped into bio-MOF-1 for ascorbic acid emission "off-on" detection in human serum.

Ascorbic acid (or widely known as vitamin C, VC) is an essential antioxidant and a free radical scavenger in human body. The appeal for reliable fluorescent nanosensors always promotes the development of VC probe. In this work, a pre-oxidized Eu-probe (denoted as Eu-NO9) was synthesized. Without VC, Eu-NO9 was nearly non-emissive owing to the inefficient ligand energy transfer (ET) to Eu ion (caused by mismatched ligand level and long distance to Eu, as revealed by single crystal analysis and emissive parameters). By adding VC, the pre-oxidized ligand was deoxidized and its ET to Eu ion became efficient (confirmed by electrochemical analysis), with Eu(III) red emission intensity obviously increased. Then Eu-NO9 was doped into a porous host bio-MOF-1 for ascorbic acid detection (denoted as Eu-NO9@MOF). The molecular sieving effect of bio-MOF-1 improved sensing selectivity, and bio-MOF-1 blue emission (421 nm) was applied as a reference for Eu(III) red emission. Linear working curves were obtained within a wide working region of 0-100 µM, with LOD of 1.7 µM. A short response time of 192 s at 25 °C was confirmed. Practical sensing plates were prepared and found applicable for VC detection in fresh human serum. The advantage of this work was the combination of a pre-oxidized probe and a porous host which gave emission "turn on" fluorescence sensing for VC with good selectivity, linear calibration curve and wide working region.

Cadmium speciation in cacao beans changes during a fermentation-like incubation.

Cadmium (Cd) concentrations in cacao often exceed food limits. Recently, it was shown that cacao bean fermentation enhances Cd solubility, opening potential for Cd mitigation in cacao products. This study was set-up to identify changes in Cd speciation during fermentation. X-Ray absorption spectroscopy (XAS) complemented with speciation calculations, were used on samples collected from high and low Cd farms, that were subjected to a fermentation-like incubation that reached high temperatures (>45 °C) and acidic pH (<5). Incubation decreased nib Cd concentration up to a factor 1.5 and changed Cd complexation in high Cd beans from sulphur to oxygen ligands, likely due to pH changes. In beans with lower Cd concentrations, Cd was complexed before and after incubation with oxygen-ligands. A combination of pH changes and/or phytate breakdown may explain the migration of Cd outward from the nib. XAS and speciation calculations proved complimentary techniques and indicated similar speciation changes during fermentation.

Oil soluble iron: Curcumin derivatives and their complex.

Curcumin dibutanoate (CUDB) is a new oil soluble bidentate ligand which shows higher stability against heat and oxidation compared to curcumin. The oil solubility of this ligand increased an order of magnitude over curcumin. This biomolecule showed high digestibility in a simulated intestinal trial and was hydrolyzed in the presence of porcine pancreatin releasing âˆ¼ 91% of the curcumin. When curcumin dibutanoate was complexed with Fe2+, Fe(CUDB)2 was formed as a new iron (II) complex. Due to the high hydrophobicity of the curcumin dibutanoate ligand, the solubility of Fe(CUDB)2 was found to be 2.8 mg/mL in canola oil. The steric hindrance afforded by the CUDB ligand, coupled with its hydrophobicity stabilized the iron (II) oxidation state within the complex compared to FeSO4·7H2O as measured by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical. Fe(CUDB)2 has potential to be a new form of oil-soluble iron supplement which co-delivers iron (II) and curcumin.

Convertase-dependent regulation of membrane-tethered and secreted ligands tunes dendrite adhesion.

During neural development, cellular adhesion is crucial for interactions among and between neurons and surrounding tissues. This function is mediated by conserved cell adhesion molecules, which are tightly regulated to allow for coordinated neuronal outgrowth. Here, we show that the proprotein convertase KPC-1 (homolog of mammalian furin) regulates the Menorin adhesion complex during development of PVD dendritic arbors in Caenorhabditis elegans. We found a finely regulated antagonistic balance between PVD-expressed KPC-1 and the epidermally expressed putative cell adhesion molecule MNR-1 (Menorin). Genetically, partial loss of mnr-1 suppressed partial loss of kpc-1, and both loss of kpc-1 and transgenic overexpression of mnr-1 resulted in indistinguishable phenotypes in PVD dendrites. This balance regulated cell-surface localization of the DMA-1 leucine-rich transmembrane receptor in PVD neurons. Lastly, kpc-1 mutants showed increased amounts of MNR-1 and decreased amounts of muscle-derived LECT-2 (Chondromodulin II), which is also part of the Menorin adhesion complex. These observations suggest that KPC-1 in PVD neurons directly or indirectly controls the abundance of proteins of the Menorin adhesion complex from adjacent tissues, thereby providing negative feedback from the dendrite to the instructive cues of surrounding tissues.

The inhibitory effects of platinum(II) complexes on amyloid aggregation: a theoretical and experimental approach.

Platinum (Pt)(II) square planar complexes are well-known anticancer drugs whose Mechanism of Action (MOA) are finely tuned by the polar, hydrophobic and aromatic features of the ligands. In the attempt to translate this tunability to the identification of potential neurodrugs, herein, four Pt(II) complexes were investigated in their ability to modulate the self-aggregation processes of two amyloidogenic models: Sup35p7-13 and NPM1264-277 peptides. In particular, phenanthriplatin revealed the most efficient agent in the modulation of amyloid aggregation: through several biophysical assays, as Thioflavin T (ThT), electrospray ionization mass spectrometry (ESI-MS) and ultraviolet-visible (UV-vis) absorption spectroscopy, this complex revealed able to markedly suppress aggregation and to disassemble small soluble aggregates. This effect was due to a direct coordination of phenanthriplatin to the amyloid, with the loss of several ligands and different stoichiometries, by the formation of π-π and π-cation interactions as indicated from molecular dynamic simulations. Presented data support a growing and recent approach concerning the repurposing of metallodrugs as potential novel neurotherapeutics.

PLP-Dependent Enzyme Methionine γ-Lyase: Insights into the Michaelis Complex from Molecular Dynamics and Free Energy Simulations.

Methionine γ-lyase (MGL) breaks down methionine, with the help of its cofactor pyridoxal-5'-phosphate (PLP), or vitamin B6. Methionine depletion is damaging for cancer cells but not normal cells, so MGL is of interest as a therapeutic protein. To increase our understanding and help engineer improved activity, we focused on the reactive, Michaelis complex M between MGL, covalently bound PLP, and substrate Met. M is not amenable to crystallography, as it proceeds to products. Experimental activity measurements helped exclude a mechanism that would bypass M. We then used molecular dynamics and alchemical free energy simulations to elucidate its structure and dynamics. We showed that the PLP phosphate has a pKa strongly downshifted by the protein, whether Met is present or not. Met binding affects the structure surrounding the reactive atoms. With Met, the Schiff base linkage between PLP and a nearby lysine shifts from a zwitterionic, keto form to a neutral, enol form that makes it easier for Met to approach its labile, target atom. The Met ligand also stabilizes the correct orientation of the Schiff base, more strongly than in simulations without Met, and in agreement with structures in the Protein Data Bank, where the Schiff base orientation correlates with the presence or absence of a co-bound anion or substrate analogue in the active site. Overall, the Met ligand helps organize the active site for the enzyme reaction by reducing fluctuations and shifting protonation states and conformational populations.

Structure-function relationships of the aldosterone receptor.

The cellular response to the adrenal steroid aldosterone is mediated by the mineralocorticoid receptor (MR), a member of the nuclear receptor superfamily of ligand-dependent transcription factors. The MR binds more than one physiological ligand with binding at the MR determined by pre-receptor metabolism of glucocorticoid ligands by 11ß hydroxysteroid dehydrogenase type 2. The MR has a wide tissue distribution with multiple roles beyond the classical role in electrolyte homeostasis including cardiovascular function, immune cell signaling, neuronal fate and adipocyte differentiation. The MR has three principal functional domains, an N-terminal ligand domain, a central DNA binding domain and a C-terminal, ligand binding domain, with structures having been determined for the latter two domains but not for the whole receptor. MR signal-transduction can be best viewed as a series of interactions which are determined by the conformation conferred on the receptor by ligand binding. This conformation then determines subsequent intra- and inter-molecular interactions. These interactions include chromatin, coregulators and other transcription factors, and additional less well characterized cytoplasmic non-genomic effects via crosstalk with other signaling pathways. This chapter will provide a review of MR structure and function, and an analysis of the critical interactions involved in MR-mediated signal transduction, which contribute to ligand- and tissue-specificity. Understanding the relevant mechanisms for selective MR signaling in terms of these interactions opens the possibility of novel therapeutic approaches for the treatment of MR-mediated diseases.

Genomically anchored vitamin D receptor mediates an abundance of bioprotective actions elicited by its 1,25-dihydroxyvitamin D hormonal ligand.

The nuclear vitamin D receptor (VDR) mediates the actions of its physiologic 1,25-dihydroxyvitamin D3 (1,25D) ligand produced in kidney and at extrarenal sites during times of physiologic and cellular stress. The ligand-receptor complex transcriptionally controls genes encoding factors that regulate calcium and phosphate sensing/transport, bone remodeling, immune function, and nervous system maintenance. With the aid of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), 1,25D/VDR primarily participates in an intricate network of feedback controls that govern extracellular calcium and phosphate concentrations, mainly influencing bone formation and mineralization, ectopic calcification, and indirectly supporting many fundamental roles of calcium. Beyond endocrine and intracrine effects, 1,25D/VDR signaling impacts multiple biochemical phenomena that potentially affect human health and disease, including autophagy, carcinogenesis, cell growth/differentiation, detoxification, metabolic homeostasis, and oxidative stress mitigation. Several health advantages conferred by 1,25D/VDR appear to be promulgated by induction of klotho, an anti-aging renal peptide hormone which functions as a co-receptor for FGF23 and, like 1,25D, regulates nrf2, foxo, mTOR and other cellular protective pathways. Among hundreds of genes for which expression is modulated by 1,25D/VDR either primarily or secondarily in a cell-specific manner, the resulting gene products (in addition to those expressed in the classic skeletal mineral regulatory tissues kidney, intestine, and bone), fall into multiple biochemical categories including apoptosis, cholesterol homeostasis, glycolysis, hypoxia, inflammation, p53 signaling, unfolded protein response and xenobiotic metabolism. Thus, 1,25D/VDR is a bone mineral control instrument that also signals the maintenance of multiple cellular processes in the face of environmental and genetic challenges.

A structural perspective of liver X receptors.

Liver X receptors α and ß are members of the nuclear receptor family, which comprise a flexible N-terminal domain, a DNA binding domain, a hinge linker, and a ligand binding domain. Liver X receptors are important regulators of cholesterol and lipid homeostasis by controlling the transcription of numerous genes. Key to their transcriptional role is synergetic interaction among the domains. DNA binding domain binds on DNA; ligand binding domain is a crucial switch to control the transcription activity through conformational change caused by ligand binding. The Liver X receptors form heterodimers with retinoid X receptor and then the liganded heterodimer may recruit other necessary transcription components to form an active transcription complex.