Crystal structure determination and dynamic studies of Mycobacterium tuberculosis Cytidine deaminase in complex with products

• Published in: Archives of biochemistry and biophysics Vol. 509; no. 1; pp. 108 - 115
• Main Authors: Sánchez-Quitian, Zilpa A., Timmers, Luís F.S.M., Caceres, Rafael A., Rehm, Jacqueline G., Thompson, Claudia E., Basso, Luiz A., de Azevedo, Walter F., Santos, Diógenes S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2011
• Subjects: Binding Sites; cell growth; crystal structure; Crystallography; Crystallography, X-Ray; cytidine; Cytidine deaminase; Cytidine Deaminase - chemistry; Cytidine Deaminase - metabolism; deamination; Deoxyuridine - metabolism; Molecular dynamics; Molecular Dynamics Simulation; Mycobacterium tuberculosis; Mycobacterium tuberculosis - chemistry; Mycobacterium tuberculosis - enzymology; Protein Binding; Tuberculosis; uridine; Uridine - metabolism; Molecular dynamics; Tuberculosis; Crystallography; Cytidine deaminase
• ISSN: 0003-9861; 1096-0384
• DOI: 10.1016/j.abb.2011.01.022

► The present study provided structural insight into the product binding patterns for CDA. ► The residues Asn45, Glu47, Ala57, Cys89, and Cys92 are pivotal to product recognition. ► Oligomeric state is essential for stabilization of the ligand. Cytidine deaminase (CDA) is a key enzyme in the pyrimidine salvage pathway. It is involved in the hydrolytic deamination of cytidine or 2′-deoxycytidine to uridine or 2′-deoxyuridine, respectively. Here we report the crystal structures of Mycobacterium tuberculosis CDA (MtCDA) in complex with uridine (2.4Å resolution) and deoxyuridine (1.9Å resolution). Molecular dynamics (MD) simulation was performed to analyze the physically relevant motions involved in the protein–ligand recognition process, showing that structural flexibility of some protein regions are important to product binding. In addition, MD simulations allowed the analysis of the stability of tetrameric MtCDA structure. These findings open-up the possibility to use MtCDA as a target in future studies aiming to the rational design of new inhibitor of MtCDA-catalyzed chemical reaction with potential anti-proliferative activity on cell growth of M. tuberculosis, the major causative agent of tuberculosis.