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Structural Insights into the Cytotoxic Mechanism of Vibrio parahaemolyticus PirAvp and PirBvp Toxins - PubMed

️Sun Jan 01 2017

Review

Structural Insights into the Cytotoxic Mechanism of Vibrio parahaemolyticus PirA^vp and PirB^vp Toxins

Shin-Jen Lin et al. Mar Drugs. 2017.

Abstract

In aquaculture, shrimp farming is a popular field. The benefits of shrimp farming include a relatively short grow-out time, high sale price, and good cost recovery. However, outbreaks of serious diseases inflict serious losses, and acute hepatopancreatic necrosis disease (AHPND) is an emerging challenge to this industry. In South American white shrimp (Penaeus vannamei) and grass shrimp (Penaeus monodon), this disease has a 70-100% mortality. The pathogenic agent of AHPND is a specific strain of Vibrio parahaemolyticus which contains PirA^vp and PirB^vp toxins encoded in the pVA1 plasmid. PirA^vp and PirB^vp have been shown to cause the typical histological symptoms of AHPND in infected shrimps, and in this review, we will focus on our structural understanding of these toxins. By analyzing their structures, a possible cytotoxic mechanism, as well as strategies for anti-AHPND drug design, is proposed.

Keywords: AHPND; Photorhabdus insect-related toxin; PirAvp; PirBvp; shrimp disease.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 1**
Crystal structures of PirA^vp (**left**) and PirB^vp (**right**) toxins. The α-helices and β-strands are shown in red and yellow, respectively. PirA^vp has a jelly-roll topology which is folded into an eight-stranded antiparallel β-barrel. PirB^vp has two domains with distinct structural features: the N-terminal of PirB^vp (PirB^vpN; residues 12–256) forms a seven-α-helix bundle; while the C-terminal (PirB^vpC; residues 279–436) contains two pairs of four-stranded antiparallel β-sheets. PirB^vpN and PirB^vpC are connected by a long loop. The PDB codes 3X0T and 3X0U were used to produce the figures for PirA^vp and PirB^vp, respectively.

**Figure 2**
A detailed comparison between structures of *B. thuringiensis* Cry and PirA^vp/PirB^vp toxins. The α-helices and â-sheets of Cry domain I and PirA^vp/PirB^vp are colored cyan and magenta, and red and yellow, respectively. (A) A comparison between Cry domain I and PirB^vpN; (B) Inside the α-helical bundle of PirB^vpN. The hydrophobic residues Leu, Ile, Val, Met, Phe, Trp and Cys are shown in yellow; (C) A comparison between Cry domain II and PirB^vpC showing the receptor binding loops of Cry domain II. A possible receptor-binding region of PirB^vpC is proposed based on a structural comparison to Cry domain II; (D) A comparison between Cry domain III and PirA^vp; (E) A potential ligand-binding site of PirA^vp. GalNAc is shown docked into the structure of PirA^vp using the docking tool iGEMDOCK [35]. Briefly, each atom of the residues and the compound was first assigned an atom type (e.g., donor or acceptor) and formal charge based on their physiochemical properties. The scoring function of iGEMDOCK was then used to measure intermolecular interactions between PirA^vp and GalNAc. In this docking model, the oxygen heteroatom of GalNAc forms hydrogen bonds with residue Lys29. Residue Glu36 yields a hydrogen bond with one of GalNAc’s hydroxyl groups. Gly38 is a non-polar residue that is sandwiched in close proximity to two hydroxyl groups. Residues Val37 and Arg84 interact with the compound via van der Waals forces. The PDB code 1CIY was used to produce the figures for the Cry toxin.

**Figure 3**
Possible binding mode and interface between PirA^vp and PirB^vp toxins. (A) Cry and proposed PirA^vp/PirB^vp complex. The PirA^vp/PirB^vp complex was predicted by reference to the positions of the three Cry domains. The possible binding regions of PirA^vp and PirB^vp are colored orange and blue; (B) The surface charges on the complex interfaces of PirA^vp and PirB^vp. Red and blue respectively indicate negatively and positively charged regions.

**Figure 4**
Strategies for designing drugs to block the cytotoxic effects of PirA^vp and PirB^vp toxins.

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Structural Insights into the Cytotoxic Mechanism of Vibrio parahaemolyticus PirAvp and PirBvp Toxins - PubMed