Structural snapshots of the catalytic cycle of the phosphodiesterase Autotaxin.
J Struct Biol
; 195(2): 199-206, 2016 08.
Article
em En
| MEDLINE
| ID: mdl-27268273
ABSTRACT
Autotaxin (ATX) is a secreted phosphodiesterase that produces the signalling lipid lysophosphatidic acid (LPA). The bimetallic active site of ATX is structurally related to the alkaline phosphatase superfamily. Here, we present a new crystal structure of ATX in complex with orthovanadate (ATX-VO5), which binds the Oγ nucleophile of Thr209 and adopts a trigonal bipyramidal conformation, following the nucleophile attack onto the substrate. We have now a portfolio of ATX structures we discuss as intermediates of the catalytic mechanism the new ATX-VO5 structure; a unique structure where the nucleophile Thr209 is phosphorylated (ATX-pThr). Comparing these to a complex with the LPA product (ATX-LPA) and with a complex with a phosphate ion (ATX-PO4), that represent the Michaelis complex of the reaction, we observe movements of Thr209, changes in the relative displacement of the zinc ions, and a water molecule that likely fulfils the second nucleophilic attack. We propose that ATX follows the associative two-step in-line displacement mechanism.
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Base de dados:
MEDLINE
Assunto principal:
Conformação Proteica
/
Lisofosfolipídeos
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Vanadatos
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Diester Fosfórico Hidrolases
Limite:
Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article