title: Dynamic mechanism for the autophosphorylation of CheA histidine kinase: molecular dynamics simulations.
abstract: The two-component system (TCS) is an important signal transduction component for most bacteria. This signaling pathway is mediated by histidine kinases via autophosphorylation between P1 and P4 domains. Taking chemotaxis protein CheA as a model of TCS, the autophosphorylation mechanism of the TCS histidine kinases has been investigated in this study by using a computational approach integrated homology modeling, ligand-protein docking, protein-protein docking, and molecular dynamics (MD) simulations. Four nanosecond-scale MD simulations were performed on the free P4 domain, P4-ATP, P4-TNPATP, and P1-P4-ATP complexes, respectively. Upon its binding to the binding pocket of P4 with a folded conformation, ATP gradually extends to an open state with help from a water molecule. Meanwhile, ATP forms two hydrogen bonds with His413 and Lys494 at this state. Because of the lower energy of the folded conformations, ATP shrinks back to its folded conformations, leading to the rupture of the hydrogen bond between ATP and Lys494. Consequently, Lys494 moves away from the pocket entrance, resulting in an open of the ATP lid of P4. It is the open state of P4 that can bind tightly to P1, where the His45 of P1 occupies a favorable position for its autophosphorylation from ATP. This indicates that ATP is not only a phosphoryl group donor but also an activator for CheA phosphorylation. Accordingly, a mechanism of the autophosphorylation of CheA is proposed as that the ATP conformational switch triggers the opening of the ATP lid of P4, leading to P1 binding tightly, and subsequently autophosphorylation from ATP to P1.
authors.affiliation: Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Graduate School, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Yechun
authors.initials: Y
authors.lastname: Xu
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shen
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Luo
authors.forename: Jiagao
authors.initials: J
authors.lastname: Chen
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.forename: Weiliang
authors.initials: W
authors.lastname: Zhu
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D001426:Bacterial Proteins / Q000737:chemistry*; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D000071677:Histidine Kinase; D006860:Hydrogen Bonding; D008565:Membrane Proteins / Q000737:chemistry*; D000072236:Methyl-Accepting Chemotaxis Proteins; D008958:Models, Molecular; D015394:Molecular Structure; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D011494:Protein Kinases / Q000737:chemistry*; D017433:Protein Structure, Secondary; D013816:Thermodynamics; D013997:Time Factors; D014867:Water / Q000737:chemistry
chemical_list: D001426:Bacterial Proteins; D008565:Membrane Proteins; D000072236:Methyl-Accepting Chemotaxis Proteins; D014867:Water; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D000071677:Histidine Kinase