5ZE4

The structure of holo- structure of DHAD complex with [2Fe-2S] cluster

Summary for 5ZE4

• Entry DOI: 10.2210/pdb5ze4/pdb
• Descriptor: Dihydroxy-acid dehydratase, chloroplastic, FE2/S2 (INORGANIC) CLUSTER, SULFATE ION, ... (6 entities in total)
• Functional Keywords: [2fe-2s] cluster, inhibit, bcaabiosynthetic pathway, lyase
• Biological source: Arabidopsis thaliana (Mouse-ear cress)
• Total number of polymer chains: 1
• Total formula weight: 61554.97

Authors

Zhou, J.,Zang, X.,Tang, Y.,Yan, Y.,Gan, J.,Wu, L. (deposition date: 2018-02-26, release date: 2018-07-18, Last modification date: 2023-11-22)

Primary citation

Yan, Y.,Liu, Q.,Zang, X.,Yuan, S.,Bat-Erdene, U.,Nguyen, C.,Gan, J.,Zhou, J.,Jacobsen, S.E.,Tang, Y.
Resistance-gene-directed discovery of a natural-product herbicide with a new mode of action.
Nature, 559:415-418, 2018

PubMed Abstract: Bioactive natural products have evolved to inhibit specific cellular targets and have served as lead molecules for health and agricultural applications for the past century. The post-genomics era has brought a renaissance in the discovery of natural products using synthetic-biology tools. However, compared to traditional bioactivity-guided approaches, genome mining of natural products with specific and potent biological activities remains challenging. Here we present the discovery and validation of a potent herbicide that targets a critical metabolic enzyme that is required for plant survival. Our approach is based on the co-clustering of a self-resistance gene in the natural-product biosynthesis gene cluster, which provides insight into the potential biological activity of the encoded compound. We targeted dihydroxy-acid dehydratase in the branched-chain amino acid biosynthetic pathway in plants; the last step in this pathway is often targeted for herbicide development. We show that the fungal sesquiterpenoid aspterric acid, which was discovered using the method described above, is a sub-micromolar inhibitor of dihydroxy-acid dehydratase that is effective as a herbicide in spray applications. The self-resistance gene astD was validated to be insensitive to aspterric acid and was deployed as a transgene in the establishment of plants that are resistant to aspterric acid. This herbicide-resistance gene combination complements the urgent ongoing efforts to overcome weed resistance. Our discovery demonstrates the potential of using a resistance-gene-directed approach in the discovery of bioactive natural products.

PubMed: 29995859
DOI: 10.1038/s41586-018-0319-4

Experimental method

X-RAY DIFFRACTION (2.11 Å)