Computational Modeling of Cellulose Synthase Heterotrimer Assembly and Identification of Antimicrobial Compounds Targeting Interface Sites in Phytophthora infestans

TL;DR

This study models the structure of a key enzyme in a plant pathogen and identifies potential antimicrobial targets that could selectively control the disease without harming plants.

Contribution

The study provides the first structural model of a heterotrimeric cellulose synthase in Phytophthora infestans and identifies pathogen-specific drug targets.

Findings

The PiCesA1–PiCesA2–PiCesA4 heterotrimer in P. infestans is stabilized by interactions between pleckstrin homology and glycosyltransferase domains.

Structure-guided docking identified potential ligands targeting interface regions unique to the pathogen's cellulose synthase.

These interface sites are absent or structurally different in plant cellulose synthases, making them suitable for selective inhibition.

Abstract

Phytophthora infestans, a devastating oomycete pathogen responsible for late blight in solanaceous crops, relies on cellulose synthase (CesA) complexes for cell wall biosynthesis and virulence. Unlike plant CesAs that form homomeric trimers, oomycete CesA complexes are hypothesized to assemble as heteromeric units, yet their structural organization remains poorly defined. Here, we employed AlphaFold-Multimer and molecular docking to resolve the structural assembly of the PiCesA1–PiCesA2–PiCesA4 heterotrimer in P. infestans and identify potential ligand-binding sites for targeted inhibition. Structural modeling revealed a conserved transmembrane architecture combined with a distinctive cytosolic organization, in which N-terminal pleckstrin homology domains play a central role in heteromeric assembly. AlphaFold-Multimer consistently predicted a stable heterotrimer stabilized by cyclic interactions between pleckstrin homology domains and glycosyltransferase-A domains, forming an extensive interface network that is spatially segregated from the conserved UDP-glucose–binding catalytic core. Structure-guided docking identified potential ligands targeting pleckstrin homology–glycosyltransferase interface regions. Notably, these sites are absent or structurally divergent in plant cellulose synthases, underscoring their potential for pathogen-selective targeting. This work advances mechanistic understanding of cellulose biosynthesis in filamentous pathogens and proposes new avenues for selective disease control in agriculture.

Figures