Molecular modeling of melatonin receptors
Melatonin receptors belong to the superfamily of G-protein coupled receptors (GPCRs), which represent a very important class of biological macromolecules. These objects are the integral membrane proteins (MPs) accommodating the wide range of influences: from light and metal cations to peptides and proteins. GPCRs mediate a great amount of processes in living organisms. Many diseases are caused by disfunctions of the systems that transduce signals via GPCRs. Thats why studying of spatial structure and, therefore, molecular mechanisms of functioning of these receptors is an important task in modern biology and medicine. To date, more than 50% of drugs are targeted on GPCRs, and this number grows rapidly.
However, experimental methods (e.g., X-ray crystallography and NMR spectroscopy) often fail to determine three-dimensional (3D) structure of GPCRs. The only exception is the bovine visual rhodopsin: its 3D X-ray structure has been determined with atomic resolution. Fig. 1 represents the TM folding of rhodopsin. It is commonly accepted now that all GPCRs share similar fold of TM domain. This reveals an opportunity to build their 3D models by means of molecular modeling.
One of the research projects in our Laboratory is targeting on building of 3D models of the human melatonin receptors MT1 and MT2. This work is being performed in collaboration with the Laboratory of Therapeutic Chemistry at the University of Lille, France. Melatonin (a derivative of tryptophan) is an important biological agent, critical for regulation of circadian rhythms; it possesses strong immunomodulator, antioxidant, and some other activities (Fig. 2).
Main objectives of the project:
Figure 3 shows homology models of MT1 and MT2 receptors with template (visual rhodopsin) structure superimposed, as well as structures of active sites binding melatonin molecule. These models were optimized using several criteria:
Optimization consisted of rotation of TM3 α-helix around its axis as a rigid body, energy minimization of receptor model complex with melatonin molecule and simultaneous assessment of model correctness according to mentioned criteria.
Optimized structures of receptor-melatonin complexes were used to delineate differences between MT1 and MT2 binding sites that draw either receptor subtype selective to some melatonin analogs. Based on the complementarity of molecular hydrophobic potential (MHP) concept, a hypothesis for selectivity of indole-type melatonin analogs was proposed. Figure 4 demonstrates application of the MHP-complementarity approach for explanation of selectivity of two MT receptors ligands: towards MT1 (fig. 4b) or MT2 (fig. 4a) subtypes.
At present, a new investigation is being held in our group: a novel method to assess the packing quality of TM domains of MPs. This approach, based on the analysis of high-resolution spatial structures of MPs, will hopefully be useful for optimization of theoretical models of MPs structures, in the first hand GPCR ones.
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