Fig. 8: TNAP’s active interaction with phosphocholine, phosphoethanolamine, PPi, and TNAPi. | Communications Biology

Fig. 8: TNAP’s active interaction with phosphocholine, phosphoethanolamine, PPi, and TNAPi.

From: TNAP dephosphorylates phosphocholine and phosphoethanolamine and participates in triglyceride transport from the liver to the bloodstream

Fig. 8

Substrate accommodation in TNAP’s active site. The best docking poses for phosphocholine and PPi obtained with the Apo enzyme are superimposed onto the TNAP structure containing Pi: A Secondary structures and key residues that define the negatively charged zones (D109 and E452) and positively charged zones (R168 and R184). B The electrostatic surface is color-coded to depict the charge distribution, with red representing negatively charged regions (the groove) and blue representing positively charged regions (the pockets). C Two examples demonstrate the orientation of phosphoethanolamine within the active site: one positioned in the positively charged pocket and the other within the negatively charged groove. D Structure of the TNAPi MLS-0038949 (MLS) and global representation of MLS interaction with TNAP’s surface. E MLS forms Pi–cation interactions between the para-di-methoxy-benzene group and Zn²⁺ (Zn2). This interaction is further stabilized by a hydrogen bond between His341 and the sulfonamide group of MLS. Additionally, cation–Pi–stacking interactions are observed between Glu342, His338, and the quinolin-3-yl group. Finally, His338 contributes to the binding through a Pi–stacking interaction with the quinolin-3-yl group of the MLS. F MLS positioning relative to the different substrates of TNAP. The structure in the presence of MLS was superimposed onto the structure containing Pi, as well as the structure used for docking with phosphocholine and PPi. This comparison highlights the steric hindrance caused by the para-di-methoxy-benzene part of the inhibitor in relation to the phosphate group of the different substrates. G Superposition of the TNAP structure (in green) containing MLS with the AlphaFold model of IAP (in gray), illustrating the interaction specificity between TNAP and the MLS. The three residues interacting with MLS, which differ between TNAP and IAP, are indicated in the respective colors of the two structures.

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