Multiscale approach to the activation and phosphotransfer mechanism of CpxA histidine kinase reveals a tight coupling between conformational and chemical steps

Sensor histidine kinases (SHKs) are an integral component of the molecular machinery that permits bacteria to adapt to widely changing environmental conditions. CpxA, an extensively studied SHK, is a multidomain homodimeric protein with each subunit consisting of a periplasmic sensor domain, a trans...

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Guardado en:
Detalles Bibliográficos
Publicado: 2018
Materias:
Coarse grain
CpxA
Histidine kinase
QM/MM
Two component system
histidine
protein CpxA
protein histidine kinase
unclassified drug
adenosine triphosphate
CpxA protein, E coli
Escherichia coli protein
protein kinase
Article
autophosphorylation
catalysis
computer simulation
enzyme activation
enzyme conformation
enzyme mechanism
enzyme phosphorylation
molecular dynamics
priority journal
chemistry
metabolism
pH
phosphorylation
protein conformation
protein domain
Adenosine Triphosphate
Escherichia coli Proteins
Histidine
Hydrogen-Ion Concentration
Molecular Dynamics Simulation
Phosphorylation
Protein Conformation
Protein Domains
Protein Kinases
Acceso en línea:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_0006291X_v498_n2_p305_Marsico
http://hdl.handle.net/20.500.12110/paper_0006291X_v498_n2_p305_Marsico
Aporte de:
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires
Descripción
Sumario:Sensor histidine kinases (SHKs) are an integral component of the molecular machinery that permits bacteria to adapt to widely changing environmental conditions. CpxA, an extensively studied SHK, is a multidomain homodimeric protein with each subunit consisting of a periplasmic sensor domain, a transmembrane domain, a signal-transducing HAMP domain, a dimerization and histidine phospho-acceptor sub-domain (DHp) and a catalytic and ATP-binding subdomain (CA). The key activation event involves the rearrangement of the HAMP-DHp helical core and translation of the CA towards the acceptor histidine, which presumably results in an autokinase-competent complex. In the present work we integrate coarse-grained, all-atom, and hybrid QM-MM computer simulations to probe the large-scale conformational reorganization that takes place from the inactive to the autokinase-competent state (conformational step), and evaluate its relation to the autokinase reaction itself (chemical step). Our results highlight a tight coupling between conformational and chemical steps, underscoring the advantage of CA walking along the DHp core, to favor a reactive tautomeric state of the phospho-acceptor histidine. The results not only represent an example of multiscale modelling, but also show how protein dynamics can promote catalysis. © 2017 Elsevier Inc.

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