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Instruments / Technical Area	Publication Details	Published	Actions
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	A parsimonious mechanism of sugar dehydration by human GDP-mannose-4,6-dehydratase Martin Pfeiffer , Catrine Johansson , Tobias Krojer , Kathryn L. Kavanagh , Udo C. T. Oppermann , Bernd Nidetzky Acs Catalysis DOI: 10.1021/acscatal.9b00064 Diamond Proposal Number(s): [1221, 7864, 9948, 15433] Show Abstract ▼ Abstract: Biosynthesis of 6-deoxy sugars, including L-fucose, involves a mechanistically complex, enzymatic 4,6-dehydration of hex-ose nucleotide precursors as the first committed step. Here, we determined pre- and post-catalytic complex structures of the human GDP-mannose 4,6-dehydratase at atomic resolution. These structures together with results of molecular dynamics simulation and biochemical characterization of wildtype and mutant enzymes reveal elusive mechanistic details of water elimination from GDP-mannose C5’’ and C6’’, coupled to NADP-mediated hydride transfer from C4’’ to C6’’. We show that concerted acid-base catalysis from only two active-site groups, Tyr179 and Glu157, promotes a syn 1,4-elimination from an enol (not an enolate) intermediate. We also show that the overall multistep catalytic reaction involves least position changes of enzyme and substrate groups; and that it proceeds under conserved exploitation of the basic (minimal) catalytic machinery of short-chain dehydrogenase/reductases.	Mar 2019
	Achieving a good crystal system for crystallographic x-ray fragment screening Patrick M. Collins , Alice Douangamath , Romain Talon , Alexandre Dias , Jose Brandao-neto , Tobias Krojer , Frank Von Delft DOI: 10.1016/bs.mie.2018.09.027 Show Abstract ▼ Abstract: The XChem facility at Diamond Light Source offers fragment screening by X-ray crystallography as a general access user program. The main advantage of X-ray crystallography as a primary fragment screen is that it yields directly the location and pose of the fragment hits, whether within pockets of interest or merely on surface sites: this is the key information for structure-based design and for enabling synthesis of follow-up molecules. Extensive streamlining of the screening experiment at XChem has engendered a very active user program that is generating large amounts of data: in 2017, 36 academic and industry groups generated 35,000 datasets of uniquely soaked crystals. It has also generated a large number of learnings concerning the main remaining bottleneck, namely, obtaining a suitable crystal system that will support a successful fragment screen. Here we discuss the practicalities of generating screen-ready crystals that have useful electron density maps, and how to ensure they will be successfully reproduced and usable at a facility outside the home lab.	Oct 2018

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