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A proof-of-concept system is presented for the hyphenation of spatial comprehensive three-dimensional liquid chromatography (3D-LC) to mass spectrometry (MS) detection via a robotic-microfluidic interface. A three-dimensional fractal microflow distributor, incorporating 16 parallel RP monolithic capillary columns arranged in a 4 × 4 configuration, was connected to an X-Y-Z robotic system. This setup facilitated the deposition of successive arrays of microdroplets onto an MS target plate. To minimize carryover during droplet deposition, a strategy was implemented in which the distance between the target plate and the capillary was gradually increased during the deposition process. System-level variation in travel time and subsequent flow rates across parallel columns was assessed and translated in retention alignment based on injection of a protein standard. The successful separation of intact proteins was demonstrated through a parallel 4 × 4 column configuration, applying MALDI-MS detection after microdroplet spotting on an MS target plate. Furthermore, the discussion encompasses high-throughput MS imaging detection within the framework of spatial 3D-LC.

01 Oct 2024·Nature Chemistry

An evolved artificial radical cyclase enables the construction of bicyclic terpenoid scaffolds via an H-atom transfer pathway

Article

Author: Stein, Alina ; Zhang, Xiang ; Vorobieva, Anastassia Andreevna ; Chen, Dongping ; Zou, Zhi ; Jakob, Roman P ; Graf, Damian Alexander ; Ward, Thomas R ; Maier, Timm ; Correia, Bruno E ; Li, Ang ; Tachibana, Ryo

While natural terpenoid cyclases generate complex terpenoid structures via cationic mechanisms, alternative radical cyclization pathways are underexplored. The metal-catalysed H-atom transfer reaction (M-HAT) offers an attractive means for hydrofunctionalizing olefins, providing access to terpenoid-like structures. Artificial metalloenzymes offer a promising strategy for introducing M-HAT reactivity into a protein scaffold. Here we report our efforts towards engineering an artificial radical cyclase (ARCase), resulting from anchoring a biotinylated [Co(Schiff-base)] cofactor within an engineered chimeric streptavidin. After two rounds of directed evolution, a double mutant catalyses a radical cyclization to afford bicyclic products with a cis-5-6-fused ring structure and up to 97% enantiomeric excess. The involvement of a histidine ligation to the Co cofactor is confirmed by crystallography. A time course experiment reveals a cascade reaction catalysed by the ARCase, combining a radical cyclization with a conjugate reduction. The ARCase exhibits tolerance towards variations in the dienone substrate, highlighting its potential to access terpenoid scaffolds.

01 Oct 2024·Structure

The future of integrated structural biology

Review

Author: Rosato, Antonio ; Lindorff-Larsen, Kresten ; Hart, Darren J. ; Márquez, José ; Sobott, Frank ; Schwalbe, Harald ; Sussman, Joel L ; Banci, Lucia ; Trantirek, Lukas ; Weiss, Manfred S. ; Hart, Darren J ; Matagne, André ; Sreeramulu, Sridhar ; Carugo, Kristina Djinovic ; Haley, Natalie ; Audergon, Pauline ; Baumeister, Wolfgang ; Steyaert, Jan ; Hauß, Thomas ; Wilmanns, Matthias ; Baldus, Marc ; Agirre, Jon ; Pierattelli, Roberta ; Celie, Patrick ; Amaro, Claudia Alen ; Weiss, Manfred S ; Sussman, Joel L. ; Felli, Isabella ; Lehtiö, Lari ; Carazo, Jose Maria ; Blackledge, Martin

Instruct-ERIC, "the European Research Infrastructure Consortium for Structural biology research," is a pan-European distributed research infrastructure making high-end technologies and methods in structural biology available to users. Here, we describe the current state-of-the-art of integrated structural biology and discuss potential future scientific developments as an impulse for the scientific community, many of which are located in Europe and are associated with Instruct. We reflect on where to focus scientific and technological initiatives within the distributed Instruct research infrastructure. This review does not intend to make recommendations on funding requirements or initiatives directly, neither at the national nor the European level. However, it addresses future challenges and opportunities for the field, and foresees the need for a stronger coordination within the European and international research field of integrated structural biology to be able to respond timely to thematic topics that are often prioritized by calls for funding addressing societal needs.

100 Deals associated with VIB-VUB Center for Structural Biology

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100 Translational Medicine associated with VIB-VUB Center for Structural Biology

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Pipeline

Pipeline Snapshot as of 14 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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