title: Crystal structure determination and dynamic studies of Mycobacterium tuberculosis Cytidine deaminase in complex with products.
abstract: 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 (2.4 Å resolution) and deoxyuridine (1.9 Å 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.
authors.affiliation: Centro de Pesquisas em Biologia Molecular e Funcional (CPBMF), Instituto Nacional de Ciência e Tecnologia em Tuberculose (INCT-TB), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Av. Ipiranga 6681, Porto Alegre, RS 90619-900, Brazil.
authors.forename: Zilpa A
authors.initials: ZA
authors.lastname: Sánchez-Quitian
authors.forename: Luís F S M
authors.initials: LF
authors.lastname: Timmers
authors.forename: Rafael A
authors.initials: RA
authors.lastname: Caceres
authors.forename: Jacqueline G
authors.initials: JG
authors.lastname: Rehm
authors.forename: Claudia E
authors.initials: CE
authors.lastname: Thompson
authors.forename: Luiz A
authors.initials: LA
authors.lastname: Basso
authors.forename: Walter F
authors.initials: WF
authors.lastname: de Azevedo
authors.forename: Diógenes S
authors.initials: DS
authors.lastname: Santos
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D003564:Cytidine Deaminase / Q000737:chemistry / Q000378:metabolism*; D003857:Deoxyuridine / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000201:enzymology*; D011485:Protein Binding; D014529:Uridine / Q000378:metabolism*
chemical_list: D003564:Cytidine Deaminase; D003857:Deoxyuridine; D014529:Uridine