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Research Highlights

the best of science obtained using CIISB Core Facilities

J. Am. Chem. Soc. 2020

Nature Index Journal

(−)-Bactobolin A and selected related natural products.

(−)-Bactobolin A (1) is a polyketide–peptide natural product first isolated in the late 1970s as a secondary metabolite of Pseudomonas sp. Early biological evaluations revealed that 1 exhibits broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens and in vivo antiproliferative effects on certain cancer cell lines. (−)-Bactobolin A (1) was subsequently identified as a strong inhibitor of protein synthesis in intact prokaryotic and eukaryotic cells, and mammalian cell-free systems.

Jakub Švenda Research Group

Significance

A stereoselective synthesis of the ribosome-binding antitumor antibiotic (−)-bactobolin A is reported. The presented approach makes effective use of (−)-quinic acid as a chiral pool starting material and substrate stereocontrol to establish the five contiguous stereocenters of (−)-bactobolin A. The key steps of the synthesis include a stereoselective vinylogous aldol reaction to introduce the unusual dichloromethyl substituent, a completely diastereoselective rhodium(II)-catalyzed C–H amination reaction to set the configuration of the axial amine, and an intramolecular alkoxycarbonylation to build the bicyclic lactone framework. The developed synthetic route was used to prepare 90 mg of (−)-bactobolin A trifluoroacetate in 10% overall yield.

Vojáčková, P., Michalska, L., Nečas, M., Shcherbakov, D., Böttger, E. C., Šponer, J., Šponer, J.E., and Švenda, J Stereocontrolled Synthesis of (−)-Bactobolin A,  J. Am. Chem. Soc.  2020, 142, 7306-7311, doi.org/10.1021/jacs.0c01554

Nucleic Acids Res. 2020

Structure of STAU1 dsRBD4 and dsRBD3/4 in complex with sARF1 SBS dsRNA. (A) Structural ensemble of the STAU1 dsRBD4–sARF1 SBS dsRNA complex. Heavy-atom superposition of the ensemble of the 20 lowest-energy structures. The protein backbone is shown in dark green and the RNA heavy atoms of the bases in orange and those of the ribose-phosphodiester backbone are shown in gold (omitting phosphate and 2-OH oxygens). (B) Schematic representation of sARF1 SBS dsRNA showing interactions of dsRBD3 as well as dsRBD4 as dotted lines. Interactions with the ribose-phosphodiester backbone are circled in dark green for dsRBD4 and light green for dsRBD3 while base interactions are shown as filled circles.

Peter J. Lukavsky Research Group

Significance

Staufen1 (STAU1) is a dsRNA binding protein mediating mRNA transport and localization, translational control and STAU1-mediated mRNA decay (SMD). The STAU1 binding site (SBS) within human ADP-ribosylation factor1 (ARF1) 3 UTR binds STAU1 and this downregulates ARF1 cytoplasmic mRNA levels by SMD. However, how STAU1 recognizes specific mRNA targets is still under debate. The structure of the ARF1 SBS–STAU1 complex, presented in this study, uncovers target recognition by STAU1. STAU1 dsRNA binding domain (dsRBD) 4 interacts with two pyrimidines and one purine from the minor groove side via helix a1, the b1–b 2 loop anchors the dsRBD at the end of the dsRNA and lysines in helix a2 bind to the phosphodiester backbone from the major groove side. STAU1 dsRBD3 displays the same binding mode with specific recognition of one guanine base. Mutants disrupting minor groove recognition of ARF1 SBS affect in vitrobinding and reduce SMD in vivo. Our data thus reveal how STAU1 recognizes minor groove features in dsRNA relevant for target selection.

 

Yadav, DP, Zigáčková, D., Zlobina, M.,  Klumpler, Beaumont, TC., Kubíčková, M., Vaňáčová, Š,  and Lukavsky, PJ.: Staufen1 reads out structure and sequence features in ARF1 dsRNA for target recognition,  Nucleic Acids Res.  2020, 48, 2091-2106, doi:10.1093/nar/gkz1163

 

More publications Research Highlights archive

Reader’s Corner

literature to read, science to follow

In this section, a distinct selection of six highly stimulating research publications and reviews published during past 6 months is presented. It is our hope that links to exciting science, which deserves attention of the structural biology community, will help you to locate gems in the steadily expanding jungle of scientific literature. You are welcome to point out to any paper you found interesting by sending a link or citation to readerscorner@ciisb.org. The section is being updated regularly.


 

Reader’s Corner Archive

Quote of June

“If I have seen further, it is by standing on the shoulders of Giants.”

Isaac Newton