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Int. J. Mol. Sci. 2015, 16(12), 29383-29397; doi:10.3390/ijms161226170

Domain Motions and Functionally-Key Residues of l-Alanine Dehydrogenase Revealed by an Elastic Network Model

College of Science, Yanshan University, Qinhuangdao 066004, China
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Academic Editor: Christo Christov
Received: 26 September 2015 / Revised: 27 November 2015 / Accepted: 2 December 2015 / Published: 9 December 2015
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Abstract

Mycobacterium tuberculosis l-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. View Full-Text
Keywords: Mycobacterium tuberculosis l-alanine dehydrogenase; domain motions; functionally-key residues; Gaussian network model; anisotropy network model; thermodynamic cycle method Mycobacterium tuberculosis l-alanine dehydrogenase; domain motions; functionally-key residues; Gaussian network model; anisotropy network model; thermodynamic cycle method
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Li, X.-Y.; Zhang, J.-C.; Zhu, Y.-Y.; Su, J.-G. Domain Motions and Functionally-Key Residues of l-Alanine Dehydrogenase Revealed by an Elastic Network Model. Int. J. Mol. Sci. 2015, 16, 29383-29397.

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