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Publication Abstract from PubMed

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 Ogamma 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.

Structural snapshots of the catalytic cycle of the phosphodiesterase Autotaxin.,Hausmann J, Keune WJ, Hipgrave Ederveen AL, van Zeijl L, Joosten RP, Perrakis A J Struct Biol. 2016 Jun 4. pii: S1047-8477(16)30108-3. doi:, 10.1016/j.jsb.2016.06.002. PMID:27268273^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.