期刊
JOURNAL OF STRUCTURAL BIOLOGY
卷 169, 期 3, 页码 304-311出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.jsb.2009.11.008
关键词
N-Carbamoylsarcosine amidase; C-D-K catalytic triad; Creatinine degradation; Crystalstructure; MM/PBSA; Molecular dynamics simulations
资金
- NIGMS NIH HHS [P50 GM062414, U54 GM074942, GM62414, GM074942, U54 GM074942-030006] Funding Source: Medline
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 angstrom. 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 1 NBA, 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. (C) 2009 Elsevier Inc. All rights reserved.
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