Crystal structure and molecular modeling study of N-carbamoylsarcosine amidase Ta0454 from Thermoplasma acidophilum |
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Authors: | Hai-Bin Luo Heping Zheng Matthew D. Zimmerman Maksymilian Chruszcz Tatiana Skarina Olga Egorova Alexei Savchenko Aled M. Edwards Wladek Minor |
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Affiliation: | 1. School of Pharmaceutical Sciences, East Campus, Sun Yat-Sen University, Guangzhou 510006, China;2. Department of Molecular Physiology and Biological Physics, University of Virginia, 1340 Jefferson Park Avenue, Charlottesville, VA 22908, USA;3. Banting and Best Department of Medical Research and Structural Genomics Consortium, 112 College Street, University of Toronto, Toronto, Ont., Canada M5G 1L6;4. Midwest Center for Structural Genomics, USA |
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Abstract: | A crystal structure of the putative N-carbamoylsarcosine amidase (CSHase) Ta0454 from Thermoplasma acidophilum was solved by single-wavelength anomalous diffraction and refined at a resolution of 2.35 Å. CSHases are involved in the degradation of creatinine. Ta0454 shares a similar fold and a highly conserved C-D-K catalytic triad (Cys123, Asp9, and Lys90) with the structures of three cysteine hydrolases (PDB codes 1NBA, 1IM5, and 2H0R). Molecular dynamics (MD) simulations of Ta0454/N-carbamoylsarcosine and Ta0454/pyrazinamide complexes were performed to determine the structural basis of the substrate binding pattern for each ligand. Based on the MD-simulated trajectories, the MM/PBSA method predicts binding free energies of ?24.5 and ?17.1 kcal/mol for the two systems, respectively. The predicted binding free energies suggest that Ta0454 is selective for N-carbamoylsarcosine over pyrazinamide, and zinc ions play an important role in the favorable substrate bound states. |
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