Solanesyl diphosphate synthase (SPS) is a key enzyme in the biosynthetic pathway of plastoquinone, the photosynthetic electron carrier, and has recently been identified as a novel target of herbicides. Fibrillin 5 (FBN5) is thought to participate in plastoquinone biosynthesis by regulating the catalytic activity of SPS. However, the molecular basis of the interaction between FBN5 and SPS and how FBN5 modulates SPS catalysis has remained unclear.

In a new collaborative study, researchers from the Institute of Biophysics of the Chinese Academy of Sciences, and Central China Normal University systematically elucidated the catalytic mechanism of OsSPS3 in rice (Oryza sativa) and the molecular basis of its interaction with OsFBN5 by combining biochemical analyses, structural biology and computational simulations.

The discovery, published in Nature Plants on January 5, provides a solid framework for understanding the regulation of plastoquinone biosynthesis.

The researchers first determined high-resolution crystal structures of OsSPS3 bound to various ligands. The asymmetric dimeric architecture of OsSPS3 suggests that the enzyme may achieve catalysis through conformational switching between the two monomers in an alternating manner.

Using a combination of complementary experimental approaches, the researchers then demonstrated a strong and highly specific direct interaction between OsFBN5 and the chloroplast-localized OsSPS3. High-resolution cryo-electron microscopy structures of the OsSPS3-FBN5 complex were subsequently solved in both the apo state and in complex with the substrate analogue GGSPP.

On the basis of these structural insights, the researchers proposed a molecular model in which OsFBN5 induces a transition of OsSPS3 from an alternating to a synchronous catalytic mechanism.

This mechanism not only explains how OsFBN5 regulates OsSPS3 function but also provides direct experimental evidence for the marked enhancement of overall catalytic efficiency by OsFBN5.

Based on the resolved high-resolution structures, the researchers further performed virtual screening and identified the clinically used anti-osteoporosis drug zoledronate (ZOL) as a compound that can effectively bind to the catalytic pocket of SPS.

In vitro enzymatic assays and crystal structure analyses revealed the binding mode of ZOL as a competitive inhibitor. Greenhouse herbicidal activity assays showed that ZOL exhibits broad-spectrum and high-efficiency herbicidal activity, indicating its potential as a lead compound for the development of new SPS-targeting herbicides.

This study not only advances the understanding of the catalytic mechanisms of photosynthesis-related enzymes and provides important insights for molecular breeding, but also lays a solid foundation for the development of novel SPS-based herbicides.

Figure: Molecular model illustrating FBN5-induced transition of SPS3 from alternating to synchronous catalysis

(Image by ZHU Ping's group)

Article link: https://www.nature.com/articles/s41477-025-02184-6

Contact: ZHU Ping

Institute of Biophysics, Chinese Academy of Sciences

Beijing 100101, China

E-mail: zhup@ibp.ac.cn

(Reported by Prof. ZHU Ping's group)