RESUMO
The tuberculous granuloma is a compact aggregate of dormant bacteria encapsulated by host macrophages. It is commonly regarded as a product of the host defense designed to isolate infectious mycobacteria. This work demonstrates that exposure of macrophages to the Mtb heat-shock protein Acr leads to overproduction of the chemokine CXCL16, allowing the mycobacterium to exploit the innate immune response. This induction of chemokine expression is hypothesized to occur through activation of ADAM proteases, providing an immunomodulatory role for Mtb Acr in the formation of the granuloma.
Assuntos
Proteína ADAM10/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Quimiocina CXCL16/metabolismo , Granuloma/microbiologia , Proteínas de Choque Térmico/imunologia , Proteínas de Membrana/metabolismo , Mycobacterium tuberculosis/metabolismo , Tuberculose/imunologia , Animais , Proteínas de Bactérias/imunologia , Linhagem Celular , Humanos , Imunidade Inata , Macrófagos/citologia , Macrófagos/imunologia , Camundongos , Modelos Biológicos , Modelos Moleculares , Mycobacterium tuberculosis/imunologia , Fagocitose , Análise Serial de Proteínas , ProteômicaRESUMO
The conformational flexibility exhibited by protein kinases poses an enormous challenge to the design of cancer therapeutics. Additionally the high degree of structural conservation within the kinase superfamily often leads to inhibitors that exhibit little selectivity and substantial cross reactivity. This work investigates the conformational changes that accompany the binding of Gleevec, or imatinib mesylate, to the tyrosine kinases c-Kit and c-Abl. Our analysis is that this fit is driven, at least in part, by the need to exclude water from solvent-exposed backbone hydrogen bonds. Both experimental and molecular modeling studies of the active state inhibitor of the tyrosine kinase c-Abl indicate that solvent exclusion also plays a role in this system.
