RESUMO
The antigen 85 (ag85) complex, composed of three proteins (ag85A, B and C), is a major protein component of the Mycobacterium tuberculosis cell wall. Each protein possesses a mycolyltransferase activity required for the biogenesis of trehalose dimycolate (cord factor), a dominant structure necessary for maintaining cell wall integrity. The crystal structure of recombinant ag85C from M. tuberculosis, refined to a resolution of 1.5 A, reveals an alpha/beta-hydrolase polypeptide fold, and a catalytic triad formed by Ser 124, Glu 228 and His 260. ag85C complexed with a covalent inhibitor implicates residues Leu 40 and Met 125 as components of the oxyanion hole. A hydrophobic pocket and tunnel extending 21 A into the core of the protein indicates the location of a probable trehalose monomycolate binding site. Also, a large region of conserved surface residues among ag85A, B and C is a probable site for the interaction of ag85 proteins with human fibronectin.
Assuntos
Aciltransferases , Antígenos de Bactérias/química , Antígenos de Bactérias/metabolismo , Fibronectinas/metabolismo , Sequência de Aminoácidos , Antígenos de Bactérias/efeitos dos fármacos , Antígenos de Bactérias/imunologia , Antituberculosos/química , Sítios de Ligação , Domínio Catalítico , Parede Celular/metabolismo , Fatores Corda/metabolismo , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Mycobacterium tuberculosis , Organofosfatos/química , Organofosfatos/metabolismo , Conformação Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/efeitos dos fármacos , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismoRESUMO
Myc and Mad family proteins regulate multiple biological processes through their capacity to influence gene expression directly. Here we show that the basic regions of Myc and Mad proteins are not functionally equivalent in oncogenesis, have separable E-box-binding activities and engage both common and distinct gene targets. Our data support the view that the opposing biological actions of Myc and Mxi1 extend beyond reciprocal regulation of common gene targets. Identification of differentially regulated gene targets provides a framework for understanding the mechanism through which the Myc superfamily governs the growth, proliferation and survival of normal and neoplastic cells.