Abstract
Human mitochondrial ornithine transporter-1 is reported in coupling with the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, which is a rare autosomal recessive disorder. For in-depth understanding of the molecular mechanism of the disease, it is crucially important to acquire the 3D structure of human mitochondrial ornithine transporter-1. Since no such structure is available in the current protein structure database, we have developed it via computational approaches based on the recent NMR structure of human mitochondrial uncoupling protein (Berardi MJ, Chou JJ, et al. Nature 2011, 476:109–113). Subsequently, we docked the ligand L-ornithine into the computational structure to search for the favorable binding mode. It was observed that the binding interaction for the most favorable binding mode is featured by six remarkable hydrogen bonds between the receptor and ligand, and that the most favorable binding mode shared the same ligand-binding site with most of the homologous mitochondrial carriers from different organisms, implying that the ligand-binding sites are quite conservative in the mitochondrial carriers family although their sequences similarity is very low with 20% or so. Moreover, according to our structural analysis, the relationship between the disease-causing mutations of human mitochondrial ornithine transporter-1 and the HHH syndrome can be classified into the following three categories: (i) the mutation occurs in the pseudo-repeat regions so as to change the region of the protein closer to the mitochondrial matrix; (ii) the mutation is directly affecting the substrate binding pocket so as to reduce the substrate binding affinity; (iii) the mutation is located in the structural region closer to the intermembrane space that can significantly break the salt bridge networks of the protein. These findings may provide useful insights for in-depth understanding of the molecular mechanism of the HHH syndrome and developing effective drugs against the disease.
Highlights
The hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome (MIM 238970), called ‘‘ornithine translocation deficiency’’, is a rare autosomal recessive disorder, characterized by mental retardation, progressive spastic paraparesis, seizures, and myoclonus epilepsy [1,2]
None of the structure-known proteins in the Protein Data Bank has more than 30% sequence similarity with the human mitochondrial ornithine transporter-1
It is not feasible to use the conventional homology modeling technique to derive the 3D structure of human mitochondrial ornithine transporter-1
Summary
The hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome (MIM 238970), called ‘‘ornithine translocation deficiency’’, is a rare autosomal recessive disorder, characterized by mental retardation, progressive spastic paraparesis, seizures, and myoclonus epilepsy [1,2]. We attempted to study the structures of wild-type and mutated mitochondrial ornithine transporter-1 by molecular modeling approaches, with an aim of providing detailed mechanism for HHH syndrome. We employed flexible molecular docking operations to identify substrate binding site in mitochondrial ornithine transporter-1 followed by molecular dynamics simulations to optimize these structural models.
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