RESUMEN
The interconversion between inactive and active protein states, traditionally described by two static structures, is at the heart of signalling. However, how folded states interconvert is largely unknown due to the inability to experimentally observe transition pathways. Here we explore the free energy landscape of the bacterial response regulator NtrC by combining computation and nuclear magnetic resonance, and discover unexpected features underlying efficient signalling. We find that functional states are defined purely in kinetic and not structural terms. The need of a well-defined conformer, crucial to the active state, is absent in the inactive state, which comprises a heterogeneous collection of conformers. The transition between active and inactive states occurs through multiple pathways, facilitated by a number of nonnative transient hydrogen bonds, thus lowering the transition barrier through both entropic and enthalpic contributions. These findings may represent general features for functional conformational transitions within the folded state.
Asunto(s)
Proteínas Bacterianas/metabolismo , Proteínas PII Reguladoras del Nitrógeno/metabolismo , Proteínas Bacterianas/química , Entropía , Enlace de Hidrógeno , Cinética , Espectroscopía de Resonancia Magnética , Cadenas de Markov , Modelos Moleculares , Simulación de Dinámica Molecular , Proteínas PII Reguladoras del Nitrógeno/química , Estructura Terciaria de Proteína , Transducción de Señal , TermodinámicaRESUMEN
The pathoetiology of Meniere's disease remains elusive. Histopathologic and imaging studies have implicated congenital or developmental abnormality of the endolymphatic duct as a likely predisposing factor to the development of endolymphatic hydrops and clinical Meniere's disease. Recently, improved high-resolution magnetic resonance imaging (MRI) protocols have allowed better demonstration of the soft tissues of the endolymphatic duct and sac. This study is a prospective evaluation of the ability of submillimeter MRI to detect the endolymphatic duct in Meniere's disease patients and control subjects. In addition, the development of the temporal bone in the region of the endolymphatic sac and duct is evaluated by measurements of the distance from the posterior semicircular canal to the subarachnoid space and the distance from the vestibule to the subarachnoid space. Visualization of the endolymphatic duct was found to be significantly less frequent in the Meniere's disease patients (29%) than in the control subjects (91%). Temporal bone measurements in the region of the endolymphatic duct showed patients with Meniere's disease to have smaller dimensions than control subjects.