Unraveling the conformational dynamics of glycerol 3-phosphate dehydrogenase, a nicotinamide adenine dinucleotide-dependent enzyme of Leishmania mexicana
| Autor: | Anderson Henrique Lima e Lima, Kauê Santana da Costa, Guelber Cardoso Gomes, Alberto Monteiro dos Santos, Ted Wilson Bichara, Jerônimo Lameira, Clauber Henrique Souza da Costa, Cláudio Nahum Alves |
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| Rok vydání: | 2020 |
| Předmět: |
chemistry.chemical_classification
biology Chemistry Allosteric regulation General Medicine Nicotinamide adenine dinucleotide Ligand (biochemistry) biology.organism_classification Leishmania Leishmania mexicana chemistry.chemical_compound Glycerol-3-phosphate dehydrogenase Enzyme Biochemistry Structural Biology Molecular targets sense organs skin and connective tissue diseases Molecular Biology |
| Zdroj: | Journal of Biomolecular Structure and Dynamics. 39:2044-2055 |
| ISSN: | 1538-0254 0739-1102 |
| DOI: | 10.1080/07391102.2020.1742206 |
| Popis: | Allosteric changes modulate the enzymatic activity, leading to activation or inhibition of the molecular target. Understanding the induced fit accommodation mechanism of a ligand in its lowest-free energy state and the subsequent conformational changes induced in the protein are important questions for drug design. In the present study, molecular dynamics (MD) simulations, binding free energy calculations, and principal component analysis (PCA) were applied to analyze the glycerol-3-phosphate dehydrogenase of Leishmania mexicana (LmGPDH) conformational changes induced by its cofactor and substrate binding. GPDH is a nicotinamide adenine dinucleotide (NAD)-dependent enzyme, which has been reported as an interesting target for drug discovery and development against leishmaniasis. Despite its relevance for glycolysis and pentose phosphate pathways, the structural flexibility and conformational motions of LmGPDH in complex with NADH and dihydroxyacetone phosphate (DHAP) remain unexplored. Here, we analyzed the conformational dynamics of the enzyme-NADH complex (cofactor), and the enzyme-NADH-DHAP complex (adduct), mapped the hydrogen-bond interactions for the complexes and pointed some structural determinants of the enzyme that emerge from these contacts to NADH and DHAP. Finally, we proposed a consistent mechanism for the conformational changes on the first step of the reversible redox conversion of dihydroxyacetone phosphate to glycerol 3-phosphate, indicating key residues and interactions that could be further explored in drug discovery. Communicated by Ramaswamy H. Sarma |
| Databáze: | OpenAIRE |
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