Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 16, Issue 12, Pages 29383-29397Publisher
MDPI
DOI: 10.3390/ijms161226170
Keywords
Mycobacterium tuberculosis L-alanine dehydrogenase; domain motions; functionally-key residues; Gaussian network model; anisotropy network model; thermodynamic cycle method
Funding
- National Natural Science Foundation of China [11204267]
- Natural Science Foundation of Hebei Province [A2014203126]
- Program for Top Young Talents of Hebei Province
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Mycobacterium tuberculosisl-alanine dehydrogenase (l-MtAlaDH) plays an important role in catalyzing l-alanine to ammonia and pyruvate, which has been considered to be a potential target for tuberculosis treatment. In the present work, the functional domain motions encoded in the structure of l-MtAlaDH were investigated by using the Gaussian network model (GNM) and the anisotropy network model (ANM). The slowest modes for the open-apo and closed-holo structures of the enzyme show that the domain motions have a common hinge axis centered in residues Met133 and Met301. Accompanying the conformational transition, both the 1,4-dihydronicotinamide adenine dinucleotide (NAD)-binding domain (NBD) and the substrate-binding domain (SBD) move in a highly coupled way. The first three slowest modes of ANM exhibit the open-closed, rotation and twist motions of l-MtAlaDH, respectively. The calculation of the fast modes reveals the residues responsible for the stability of the protein, and some of them are involved in the interaction with the ligand. Then, the functionally-important residues relevant to the binding of the ligand were identified by using a thermodynamic method. Our computational results are consistent with the experimental data, which will help us to understand the physical mechanism for the function of l-MtAlaDH.
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