Molecular dynamics simulations reveal a novel mechanism for ATP inhibition of insulin degrading enzyme.
Regulation of brain levels of the Amyloid-β 42 (Aβ42) polypeptide by IDE has recently been linked with possible routes for new therapies against Alzheimer's disease (AD). One important aspect is the regulatory mechanism of IDE by ATP, which is an IDE activator in degrading small peptides and an inhibitor in degrading larger peptides, such as Aβ42. This relationship was investigated in this study. We present molecular dynamics simulations of Aβ42 complexed with IDE, in the absence or presence of either ATP or excess Na(+) and Cl(-) ions. Results suggest a previously unreported inhibition mechanism that depends on charge-induced structural modifications in the active site and interactions simultaneously involving ATP, Aβ42, and IDE. Such interactions exist only when both ATP and Aβ42 are simultaneously present in the catalytic chamber. This mechanism results in allosteric, noncompetitive inhibition with apparent decrease of substrate affinity, in accordance with experiment.
Departamento de Química Fundamental, Universidade Federal de Pernambuco , Av. Jornalista Aníbal Fernandes, s/n, Cidade Universitária, Recife-PE Brazil , 50.740-560.
Carlos H B
CH
da Cruz
Gustavo
G
Seabra
D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology*; D000494:Allosteric Regulation / Q000187:drug effects; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D007339:Insulysin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011480:Protease Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D059748:Proteolysis / Q000187:drug effects; D013816:Thermodynamics; D013997:Time Factors
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011480:Protease Inhibitors; C075222:amyloid beta-protein (1-42); D000255:Adenosine Triphosphate; D007339:Insulysin