6B02

Crystal structure of CfFPPS2 (apo form), a lepidopteran type-II farnesyl diphosphate synthase

Summary for 6B02

• Entry DOI: 10.2210/pdb6b02/pdb
• Related: 6B04 6B06 6B07
• Descriptor: Farnesyl diphosphate synthase (1 entity in total)
• Functional Keywords: juvenile hormone, farnesyl diphosphate synthase, transferase
• Biological source: Choristoneura fumiferana (Spruce budworm moth)
• Total number of polymer chains: 2
• Total formula weight: 78322.10

Authors

Picard, M.-E.,Cusson, M.,Shi, R. (deposition date: 2017-09-13, release date: 2017-12-13, Last modification date: 2023-10-04)

Primary citation

Picard, M.E.,Nisole, A.,Beliveau, C.,Sen, S.,Barbar, A.,Shi, R.,Cusson, M.
Structural characterization of a lepidopteran type-II farnesyl diphosphate synthase from the spruce budworm, Choristoneura fumiferana: Implications for inhibitor design.
Insect Biochem. Mol. Biol., 92:84-92, 2017

PubMed Abstract: Farnesyl diphosphate synthase (FPPS) is an enzyme from the class of short chain (E)-prenyltransferases that catalyzes the condensation of two molecules of isopentenyl diphosphate (IPP, C) with dimethylallyl diphosphate (DMAPP, C) to generate the C product FPP. In insects, FPPS plays a key role in the biosynthesis of the morphogenetic and gonadotropic "juvenile hormone" (JH). Lepidopteran genomes encode two very distinct FPPS paralogs, one of which ("type-II") is expressed almost exclusively in the JH-producing glands, the corpora allata. This paralog has been hypothesized to display structural features that enable the binding of the bulkier precursors required for the biosynthesis of lepidopteran ethyl-branched JHs. Here, we report on the first crystal structures of an insect FPPS solved to date. Apo, ligand-bound, and inhibitor-bound structures of type-II FPPS (FPPS2) from the spruce budworm, Choristoneura fumiferana (Order: Lepidoptera), were obtained. Comparison of apo and inhibitor-bound enzymes revealed differences in both inhibitor binding and structural plasticity of CfFPPS2 compared to other FPPSs. Our data showed that IPP is not essential to the closure of the C-terminal tail. Ortho-substituted pyridinium bisphosphonates, previously shown to inhibit CfFPPS2, bound to the allylic site, as predicted; however, their alkyl groups were oriented towards the homoallylic binding site, with the bulkier propyl-substituted inhibitor penetrating deeply into the IPP binding pocket. The current study sheds light on the structural basis of substrate specificity of type-II FPPS of the spruce budworm. Through a comparison with other inhibitor-bound FPPSs, we propose several approaches to improve inhibitor selectivity and potency.

PubMed: 29183817
DOI: 10.1016/j.ibmb.2017.11.011

Experimental method

X-RAY DIFFRACTION (2.82 Å)